Substituted heteroaromatic pyrazolo-pyridines and their use as glun2b receptor modulators

ABSTRACT

Substituted Pyrazolo-pyridines as GluN2B receptor ligands. Such compounds may be used in GluN2B receptor modulation and in pharmaceutical compositions and methods for the treatment of disease states, disorders, and conditions mediated by GluN2B receptor activity.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the priority benefit of U.S. provisionalapplication No. 62/861,665, filed Jun. 14, 2019, the contents of whichare incorporated herein in their entireties by reference thereto.

FIELD OF THE INVENTION

The present invention is related to compounds having GluN2B modulatingproperties, pharmaceutical compositions comprising these compounds,chemical processes for preparing these compounds and their use in thetreatment of diseases associated with GluN2B receptor activity inanimals, in particular humans.

BACKGROUND OF THE INVENTION

Glutamate is one of the major excitatory neurotransmitters that iswidely spread in the brain. First indication of its role as anexcitatory messenger was in the 1950's when it was observed thatintravenous administration of glutamate induces convulsions. However,the detection of the whole glutamatergic neurotransmitter system withits various receptors did not take place before the 1970's and 1980'swhen numerous antagonists were developed or, as in the case of PCP andketamine, were identified as antagonists. Finally, in the 1990'smolecular biology provided the tools for the classification of theglutamatergic receptors.

N-methyl-D-aspartate (NMDA) receptors are a subtype of ionotropicglutamate receptors that mediate excitatory synaptic transmission in thebrain. NMDA receptors are ubiquitously distributed throughout the brainand play a key role in synaptic plasticity, synaptogenesis,excitotoxicity, memory acquisition and learning. NMDA receptors aredistinct from other major subtypes of ionotropic glutamate receptors(AMPA and kainate receptors) in that they are blocked by Mg²⁺ at restingmembrane potentials, are highly Ca²⁺ permeable, and requireco-activation by two distinct neurotransmitters: glutamate and glycine(or D-serine) (Traynelis S F et al., Pharmacol Rev. 2010; 62(3):405-96).The influx of Ca²⁺ through NMDA receptors triggers signaling cascadesand regulates gene expression that is critical for different forms ofsynaptic plasticity including both long-term potentiation of synapseefficacy (LTP) (Berberich S et al., Neuropharmacology 2007; 52(1):77-86)and long-term depression (LTD) (Massey, P V et al., J Neurosci. 2004Sep. 8; 24(36):7821-8).

The vast majority of the mammalian NMDA receptors form a heterotetramermade of two obligatory GluN1 units and two variable GluN2 receptorsubunits encoded by the GRIN1 gene and one of four GRIN2 genes,respectively. One or both GluN2 subunits can be potentially replaced bya GluN3A or a GluN3B subunit. The GRIN1 gene product has 8 splicevariants while there are 4 different GRIN2 genes (GRIN2A-D) encodingfour distinct GluN2 subunits. The glycine binding site is present on theGluN1 subunit and the glutamate binding site is present on the GluN2subunit.

The GluNR2 subunits play a dominant role in determining the functionaland pharmacological properties of the NMDA receptor assembly and exhibitdistinct distribution in different areas of the brain. For instance,GluN2B subunits are expressed primarily in the forebrain in the adultmammalian brain (Paoletti P et al., Nat Rev Neurosci. 2013;14(6):383-400; Watanabe M et al., J Comp Neurol. 1993; 338(3):377-90)and are implicated in learning, memory processing, mood, attention,emotion and pain perception (Cull-Candy S et al., Curr Opin Neurobiol.2001; 11(3):327-35).

Compounds that modulate GluN2B-containing NMDA receptor function can beuseful in treatment of many neurological and psychiatric disordersincluding but not limited to bipolar disorder (Martucci L et al.,Schizophrenia Res, 2006; 84(2-3):214-21), major depressive disorder(Miller O H et al., eLife. 2014; 3:e03581; Li N et al., Biol Psychiatry.2011; 69(8):754-61), treatment-resistant depression (Preskorn S H et al.J Cin Psychopharmacol. 2008; 28(6):631-7) and ther mood disorders(including schizophrenia (Grimwood S et al., Neuroreport. 1999;10(3):461-5; Weickert C S et al. Molecular Psychiatry (2013) 18,1185-1192), ante- and postpartum depression, seasonal affective disorderand the like), Alzheimer's disease (Hanson J E et al., Neurobiol Dis.2015; 74:254-62; Li S et al., J Neurosci. 2011; 31(18):6627-38) andother dementias (Orgogozo J M et al. Stroke 2002, 33: 1834-1839),Parkinson's disease (Duty S, CNS Drugs. 2012; 26(12):1017-32;Steece-Collier K et al., Exp Neurol. 2000; 163(1):239-43; Leaver K R etal. Cin Exp Pharmacol Physiol. 2008; 35(11):1388-94), Huntington'schorea (Tang T S et al., Proc Natl Acad Sci USA. 2005; 102(7):2602-7; LiL et al., J Neurophysiol. 2004; 92(5):2738-46), multiple sclerosis(Grasselli G et al., Br J Pharmacol. 2013; 168(2):502-17; Farjam M etal., Iran J Pharm Res. 2014; 13(2):695-705), cognitive impairment (WangD et al. 2014, Expert Opin Ther Targets Expert Opin Ther Targets. 2014;18(10):1121-30), head injury (Bullock M R et al., Ann N Y Acad Sci.1999; 890:51-8), spinal cord injury, stroke (Yang Y et al., J Neurosurg.2003; 98(2):397-403), epilepsy (Naspolini A P et al., Epilepsy Res. 2012June; 100(1-2):12-9), movement disorders (e.g. dyskinesias) (MorissetteM et al., Mov Disord. 2006; 21(1):9-17), various neurodegenerativediseases (e.g. amyotrophic lateral sclerosis (Fuller P I et al.,Neurosci Lett. 2006; 399(1-2):157-61) or neurodegeneration associatedwith bacterial or chronic infections), glaucoma (Naskar R et al. SeminOphthalmol. 1999 September; 14(3):152-8), pain (e.g. chronic, cancer,post-operative and neuropathic pain (Wu L J and Zhuo M,Neurotherapeutics. 2009; 6(4):693-702), diabetic neuropathy, migraine(Peeters M et al., J Pharmacol Exp Ther. 2007; 321(2):564-72), cerebralischemia (Yuan H et al., Neuron. 2015; 85(6):1305-18), encephalitis(Dalmau J. et al., Lancet Neurol. 2008; 7(12):1091-8.), autism andautism spectrum disorders (Won H. et al., Nature. 2012;486(7402):261-5), memory and learning disorders (Tang, Y. P. et al.,Nature. 1999; 401(6748):63-9), obsessive compulsive disorder (Arnold P Det al., Psychiatry Res. 2009; 172(2):136-9.), attention deficithyperactivity disorder (ADHD) (Dorval K M et al., Genes Brain Behav.2007; 6(5):444-52), PTSD (Haller J et al. Behav Pharmacol. 2011;22(2):113-21; Leaderbrand K et al. Neurobiol Learn Mem. 2014;113:35-40), tinnitus (Guitton M J, and Dudai Y, Neural Plast. 2007;80904; Hu S S et al. 2016; 273(2): 325-332), sleep disorders (likenarcolepsy or excessive daytime sleepiness, patent WO 2009058261 A1),vertigo and nystagmus (Straube A. et al., Curr Opin Neurol. 2005;18(1):11-4; Starck M et al. J Neurol. 1997 January; 244(1):9-16),anxiety autoimmunological disorders like neuropsychiatric systemic lupuserythematosus (Kowal C et al. Proc. Natl. Acad. Sci. U.S.A. 2006; 103,19854-19859) and addictive illnesses (e.g. alcohol addiction, drugaddiction) (Nagy J, 2004, Curr Drug Targets CNS Neurol Disord 2004;3(3):169-79; Shen H et al., Proc Natl Acad Sci USA. 2011;108(48):19407-12).

In view of the clinical importance of GluN2B, the identification ofcompounds that modulate GluN2B receptor function represents anattractive avenue into the development of new therapeutic agents. Suchcompounds are provided herein.

SUMMARY OF THE INVENTION

The invention is directed to the general and preferred embodimentsdefined, respectively, by the independent and dependent claims appendedhereto, which are incorporated by reference herein. One aspect of thisinvention concerns compounds of Formula (I):

wherein

R¹ is H, halo, or CH₃;

Ar¹ is selected from the group consisting of:

-   -   (a) phenyl substituted with one member selected from the group        consisting of: halo, C₁₋₆alkyl, OC₁₋₆alkyl, C₁₋₆perhaloalkyl,        and OC₁₋₆perhaloalkyl;    -   (b) phenyl substituted with two or three members each        independently selected from the group consisting of: halo,        C₁₋₆alkyl, C₁₋₆perhaloalkyl, and OC₁₋₆perhaloalkyl, and CO₂H;        and    -   (c) thienyl substituted with a member selected from the group        consisting of: halo, C₁₋₆alkyl, and C₁₋₆perhaloalkyl; and        pyridine substituted with CF₃; and

R² is selected from the group consisting of:

-   -   (d)

-   -   wherein        -   R^(a) is halo, C₁₋₆alkyl or CN;        -   R^(b) is H or C₁₋₂alkyl;        -   R^(c) is selected from the group consisting of: H,            C₁₋₆alkyl, C₁₋₆perhaloalkyl, CH₂OH, OC₁₋₆alkyl, OH, NH₂,            NH(CH₃), N(CH₃)₂, NH(C═O)CH₃, cyclopropyl, and phenyl;        -   X¹ is NCH₃, S or O;        -   X² is O, NH or NCH₃;        -   X³ is O or S;        -   X⁴ is NH or O;        -   X⁵ is NCH₃ or O;        -   X⁶ is NCH₃ or S;        -   and n is 2;    -   (e) phenyl; phenyl substituted with one or two members        independently selected from the group consisting of: halo,        OC₁₋₆alkyl, C₁₋₆perhaloalkyl, and CN; and    -   (f)

-   -   wherein        -   R^(d) is H or OC₁₋₆alkyl;        -   R^(e) is a member selected from the group consisting of: H,            halo, C₁₋₆alkyl, C₁₋₆perhaloalkyl, OC₁₋₆alkyl,            OC₁₋₆perhaloalkyl, and CN; and        -   R^(f) is H, C₁₋₆alkyl or OC₁₋₆alkyl;            and pharmaceutically acceptable salts, stereoisomers,            isotopic variants, N-oxides, or solvates of compounds of            Formula (I).

Further embodiments are provided by pharmaceutically acceptable salts ofcompounds of Formulas (I), pharmaceutically acceptable prodrugs ofcompounds of Formula (I), and pharmaceutically active metabolites ofcompounds of Formula (I).

In certain embodiments, the compounds of Formula (I) are compoundsselected from those species described or exemplified in the detaileddescription below.

In a further aspect, the invention relates to enantiomers anddiastereomers of the compounds of Formula (I), as well as thepharmaceutically acceptable salts.

In a further aspect, the invention relates to pharmaceuticalcompositions for treating a disease, disorder, or medical conditionmediated by GluN2B receptor activity, comprising an effective amount ofat least one compound selected from compounds of Formula (I),pharmaceutically acceptable salts of compounds of Formula (I),pharmaceutically acceptable prodrugs of compounds of Formula (I), andpharmaceutically active metabolites of Formula (I).

Pharmaceutical compositions according to the invention may furthercomprise one or more pharmaceutically acceptable excipients.

In another aspect, the chemical embodiments of the present invention areuseful as GluN2B receptor modulators. Thus, the invention is directed toa method for modulating GluN2B receptor activity, including when suchreceptor is in a subject, comprising exposing GluN2B receptor to aneffective amount of at least one compound selected from compounds ofFormula (I), pharmaceutically acceptable salts of compounds of Formula(I), pharmaceutically acceptable prodrugs of compounds of Formula (I),and pharmaceutically active metabolites of compounds of Formula (I).

In another aspect, the invention is directed to a method of treating asubject suffering from, or diagnosed with a disease, disorder, ormedical condition mediated by GluN2B receptor activity, comprisingadministering to the subject in need of such treatment an effectiveamount of at least one compound selected from compounds of Formula (I),pharmaceutically acceptable salts of compounds of Formula (I),pharmaceutically acceptable prodrugs of compounds of Formula (I), andpharmaceutically active metabolites of compounds of Formula (I).Additional embodiments of methods of treatment are set forth in thedetailed description.

In another aspect, the method of studying isotopically labeled compoundsin metabolic studies (preferably with ¹⁴C), reaction kinetic studies(with, for example ²H or ³H), detection or imaging techniques [such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT)] including drug or substrate tissue distributionassays, or in radioactive treatment of patients. For example, an ¹⁸F or¹¹C labeled compound may be particularly preferred for PET or SPECTstudies.

Additional embodiments of this invention include methods of makingcompounds of Formula (I), pharmaceutically acceptable salts of compoundsof Formula (I), pharmaceutically acceptable prodrugs of compounds ofFormula (I), and pharmaceutically active metabolites of Formula (I).

An object of the present invention is to overcome or ameliorate at leastone of the disadvantages of the conventional methodologies and/or priorart, or to provide a useful alternative thereto.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

DETAILED DESCRIPTION OF INVENTION

In one aspect, provided herein are compounds of Formula (I),

wherein

R¹ is H, halo, or CH₃;

Ar¹ is selected from the group consisting of:

-   -   (a) phenyl substituted with one member selected from the group        consisting of: halo, C₁₋₆alkyl, OC₁₋₆alkyl, C₁₋₆perhaloalkyl,        and OC₁₋₆perhaloalkyl;    -   (b) phenyl substituted with two or three members each        independently selected from the group consisting of: halo,        C₁₋₆alkyl, C₁₋₆perhaloalkyl, OC₁₋₆perhaloalkyl, and CO₂H; and    -   (c) thienyl substituted with a member selected from the group        consisting of: halo, C₁₋₆alkyl, and C₁₋₆perhaloalkyl; and        pyridine substituted with CF₃; and

R² is selected from the group consisting of:

-   -   (d)

-   -   wherein        -   R^(a) is halo, C₁₋₆alkyl or CN;        -   R^(b) is H or C₁₋₂alkyl;        -   R^(c) is selected from the group consisting of: H,            C₁₋₆alkyl, C₁₋₆perhaloalkyl, CH₂OH, C₁₋₆alkyl, OH, NH₂,            NH(CH₃), N(CH₃)₂, NH(C═O)CH₃, cyclopropyl, and phenyl;        -   X¹ is NCH₃, S or O;        -   X² is O, NH or NCH₃;        -   X³ is O or S;        -   X⁴ is NH or O;        -   X⁵ is NCH₃ or O;        -   X⁶ is NCH₃ or S;        -   and n is 2;    -   (e) phenyl; phenyl substituted with one or two members        independently selected from the group consisting of: halo,        OC₁₋₆alkyl, C₁₋₆perhaloalkyl, and CN; and    -   (f)

-   -   wherein        -   R^(d) is H or OC₁₋₆alkyl;        -   R^(e) is a member selected from the group consisting of: H,            halo, C₁₋₆alkyl, C₁₋₆perhaloalkyl, OC₁₋₆alkyl,            OC₁₋₆perhaloalkyl, and CN; and        -   R^(f) is H, C₁₋₆alkyl or OC₁₋₆alkyl;            and pharmaceutically acceptable salts, stereoisomers,            isotopic variants, N-oxides, or solvates thereof.

An additional embodiment of the invention is a compound of Formula (I)wherein R¹ is H.

An additional embodiment of the invention is a compound of Formula (I)wherein R¹ is F.

An additional embodiment of the invention is a compound of Formula (I)wherein R¹ is CH₃.

An additional embodiment of the invention is a compound of Formula (I)wherein Ar is

An additional embodiment of the invention is a compound of Formula (I)wherein Ar¹ is phenyl substituted with F, Cl, CH₃, OCH₃, CF₂H, CF₃,CF₂CH₃, or OCHF₂.

An additional embodiment of the invention is a compound of Formula (I)wherein Ar¹ is

An additional embodiment of the invention is a compound of Formula (I)wherein Ar¹ is phenyl substituted with two or three membersindependently selected from the group consisting of: F, Cl, Br, CH₃,CF₂H, CF₃, CF₂CH₃, or OCHF₂.

An additional embodiment of the invention is a compound of Formula (I)wherein Ar¹ is

An additional embodiment of the invention is a compound of Formula (I)wherein R^(a) is F, CH₃ or CN.

An additional embodiment of the invention is a compound of Formula (I)wherein R^(b) is H, CH₃ or CH₂CH₃.

An additional embodiment of the invention is a compound of Formula (I)wherein R^(b) is H or CH₃.

An additional embodiment of the invention is a compound of Formula (I)wherein R^(c) is H, CH₃, CH₂CH₃, CF₃, OCH₃, OH, NH₂, NH(CH₃), N(CH₃)₂,NH(C═O)CH₃, cyclopropyl, or phenyl.

An additional embodiment of the invention is a compound of Formula (I)wherein R^(d) is H.

An additional embodiment of the invention is a compound of Formula (I)wherein R^(d) is OCH₃.

An additional embodiment of the invention is a compound of Formula (I)wherein R^(e) is H, Br, Cl, F, CH₃, CF₂H, CF₃, OCH₃, OCF₂H, or CN.

An additional embodiment of the invention is a compound of Formula (I)wherein R^(f) is H, CH₃, or OCH₃.

An additional embodiment of the invention is a compound of Formula (I)wherein X¹ is NCH₃.

An additional embodiment of the invention is a compound of Formula (I)wherein X¹ is O.

An additional embodiment of the invention is a compound of Formula (I)wherein X¹ is S.

An additional embodiment of the invention is a compound of Formula (I)wherein X² is O.

An additional embodiment of the invention is a compound of Formula (I)wherein X² is NH.

An additional embodiment of the invention is a compound of Formula (I)wherein X² is NCH₃.

An additional embodiment of the invention is a compound of Formula (I)wherein X³ is O.

An additional embodiment of the invention is a compound of Formula (I)wherein X³ is S.

An additional embodiment of the invention is a compound of Formula (I)wherein X⁴ is NH.

An additional embodiment of the invention is a compound of Formula (I)wherein X⁴ is O.

An additional embodiment of the invention is a compound of Formula (I)wherein X⁵ is NCH₃.

An additional embodiment of the invention is a compound of Formula (I)wherein X⁵ is O.

An additional embodiment of the invention is a compound of Formula (I)wherein X⁶ is NCH₃.

An additional embodiment of the invention is a compound of Formula (I)wherein X⁶ is S.

An additional embodiment of the invention is a compound of Formula (I)wherein R² is

An additional embodiment of the invention is a compound of Formula (I)wherein R² is

An additional embodiment of the invention is a compound of Formula (I)wherein R² is

An additional embodiment of the invention is a compound of Formula (I)wherein R² is

An additional embodiment of the invention is a compound of Formula (I)wherein R² is

An additional embodiment of the invention is a compound of Formula (I)wherein R² is

An additional embodiment of the invention is a compound of Formula (I)wherein R² is

An additional embodiment of the invention is a compound of Formula (I)wherein R² is

An additional embodiment of the invention is a compound of Formula (I)wherein R² is

An additional embodiment of the invention is a compound of Formula (I)wherein R² is

An additional embodiment of the invention is a compound of Formula (I)wherein

An additional embodiment of the invention is a compound of Formula (I)wherein

An additional embodiment of the invention is a compound of Formula (I)having the Formula (IA):

-   -   wherein    -   R¹ is H, F, or CH₃;    -   HAL is F or Cl;    -   R^(g) is selected from the group consisting of: H, Cl, CH₃,        CF₂H, CF₂CH₃, CF₃, and OCF₂H; and    -   Ring A is:        -   (a)

-   -   -    wherein R^(a) is F, CH₃ or CN;

-   -   -   X¹ is O, NCH₃ or S;        -   X³ is O or S;        -   X⁴ is NH or O;        -   X⁵ is NCH₃ or O;        -   R^(b) is H, CH₃, or CH₂CH₃;        -   R^(c) is selected from the group consisting of: H, CH₃,            CH₂CH₃, CH(CH₃)₂, CF₃, CHF₂, OCH₃, OH, NH₂, NH(CH₃),            N(CH₃)₂, NH(C═O)CH₃, cyclopropyl, and phenyl;        -   R^(d) is H or OCH₃; and        -   R^(f) is H, CH₃ or OCH₃;        -   and pharmaceutically acceptable salts, solvates, or N-oxides            thereof.

An additional embodiment of the invention is a compound of Formula (IA),wherein ring A is

An additional embodiment of the invention is a compound of Formula (I)having the Formula (IB):

-   -   wherein    -   R¹ is H, F, or CH₃;    -   R^(e) is a member selected from the group consisting of: H, Br,        Cl, F, C₁₋₄alkyl, C₁₋₄perhaloalkyl, OC₁₋₄alkyl,        OC₁₋₄perhaloalkyl, and CN; and    -   Ar¹ is selected from the group consisting of:        -   (a) phenyl substituted with one member selected from the            group consisting of: Cl, F, C₁₋₄alkyl, OC₁₋₄alkyl,            C₁₋₄perhaloalkyl, and OC₁₋₄perhaloalkyl;        -   (b) phenyl substituted with two or three members each            independently selected from the group consisting of: Br, Cl,            F, C₁₋₄alkyl, C₁₋₄perhaloalkyl, and OC₁₋₄perhaloalkyl; and        -   (c) thienyl substituted with a member selected from the            group consisting of: Cl, CH₃, and CHF₂, CF₃.

An additional embodiment of the invention is a compound of Formula (IB),wherein R¹ is H, and R^(e) is H or F.

A further embodiment of the current invention is a compound as shownbelow in Table 1.

Ex # Compound Name 11-(Pyrimidin-2-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;21-[(5-Bromo-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 35-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile; 41-[(2-Methylpyrimidin-5-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 51-(Pyrazin-2-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;61-(Pyrimidin-4-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;72-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-oxadiazole; 82-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-oxazole; 92-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-oxazole; 102-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 116-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridine; 126-[3-(1,1-Difluoroethyl)phenyl]-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine;136-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-methyl-4H-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridine; 141-[(3-Methyl-1H-pyrazol-5-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 155-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-N-methyl-1,3,4-thiadiazol-2-amine; 165-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazol-2-amine; 175-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazol-2-ol; 185-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazol-2-amine; 19N-(5-((6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-1,3,4-thiadiazol-2-yl)acetamide; 203-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,2,4-oxadiazole; 211-Benzyl-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 221-[(3-Fluorophenyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 233-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]benzonitrile; 241-[(4-Methoxyphenyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 25 6-[3-(Trifluoromethyl)phenyl]-1-[[4-(trifluoromethyl)phenyl]methyl]pyrazolo[4,3-b]pyridine; 263-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]benzonitrile; 276-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(3,5-difluorophenyl)methyl]pyrazolo[4,3-b]pyridine; 283-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-fluoro-benzonitrile; 293-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]benzonitrile; 306-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(3,5-difluorophenyl)methyl]pyrazolo[4,3-b]pyridine; 313-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-fluoro-benzonitrile; 326-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-methyl-2-thienyl)methyl]pyrazolo[4,3-b]pyridine; 336-(3-(Difluoromethyl)-4-fluorophenyl)-1-((5-fluorothiophen-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridine; 345-((6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)thiophene-2-carbonitrile; 356-[3-(1,1-Difluoroethyl)phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridine; 361-[(1-Methylimidazol-4-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 37 1-[(2,5-Dimethylpyrazol-3-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 386-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridine; 396-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridine; 406-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridine; 416-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridine; 425-[[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-isoxazole;433-[[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-isoxazole;443-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]isoxazole;453-[[6-[3-(1,1-Difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-isoxazole; 464-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazole;47 5-Methyl-3-[[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]isoxazole; 485-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-2-methyl-oxazole; 492-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-oxazole; 505-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]isoxazole; 513-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]isoxazole; 525-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-isoxazole; 533-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-isoxazole; 545-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-2-methyl-oxazole; 554-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-2-methyl-oxazole; 563-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-4-methyl-isoxazole; 574-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3,5-dimethyl-isoxazole; 583-[[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-isoxazole; 593-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-isoxazole; 605-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-2-methyl-oxazole; 612-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-oxazole; 623-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-isoxazole; 635-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-2-methyl-oxazole; 645-Methyl-3-[[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]isothiazole; 652-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-thiazole; 662-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-4-methyl-thiazole; 674-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-2-methyl-thiazole; 682-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-thiazole; 692-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-thiazole; 702-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-thiazole; 71 1-[(1-Methyl-1,2,4-triazol-3-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 726-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(1-methyltriazol-4-yl)methyl]pyrazolo[4,3-b]pyridine; 736-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridine; 746-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(4-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridine; 756-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(4,5-dimethyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridine; 766-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-ethyl-4-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridine; 772-[[6-(5-Chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 782-Methyl-5-[[6-[5-(trifluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-oxadiazole; 792-[[6-[5-(Difluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 805-[[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole; 815-[[6-(3-Methoxyphenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole; 822-[[6-[3-(1,1-Difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 832-[[6-[3-(1,1-Difluoroethyl)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 843-Methyl-5-[[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,2,4-oxadiazole; 852-Methyl-5-[[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-oxadiazole; 865-Methyl-3-[[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,2,4-oxadiazole; 875-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,2,4-oxadiazole; 882-Methyl-5-[[6-[2-(trifluoromethyl)-4-pyridyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-oxadiazole; 892-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 902-[[3-Fluoro-6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 912-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-(trifluoromethyl)-1,3,4-oxadiazole; 922-[[6-(3-Chloro-4-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 932-[[6-(3-Chloro-4-fluoro-phenyl)-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 942-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-oxadiazole; 955-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole; 962-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 973-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,2,4-oxadiazole; 983-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-4-methyl-1,2,5-oxadiazole; 992-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-oxadiazole; 1002-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-isopropyl-1,3,4-oxadiazole; 1015-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-N,N-dimethyl-1,3,4-oxadiazol-2-amine; 1022-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-(trifluoromethyl)-1,3,4-oxadiazole; 1032-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-phenyl-1,3,4-oxadiazole; 1042-[[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 1052-[[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 1062-[[6-[4-Chloro-3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 1072-[[6-[4-Chloro-3-(difluoromethyl)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 1085-[[6-[3-Fluoro-5-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole; 1095-[[6-[2-Fluoro-5-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole; 1105-[[6-[4-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole; 1115-[[6-[2-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole; 1125-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole; 1132-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 1143-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,2,4-oxadiazole; 1152-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-(trifluoromethyl)-1,3,4-oxadiazole; 1162-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 1172-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 1182-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 1192-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-(trifluoromethyl)-1,3,4-oxadiazole; 1204-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]thiadiazole; 1212-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazole; 1222-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole; 1232-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole; 1242-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-methyl-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole; 1252-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-ethyl-1,3,4-thiadiazole; 1265-((6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-N-methyl-1,3,4-thiadiazol-2-amine; 1272-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methoxy-1,3,4-thiadiazole; 128N-(5-((6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-1,3,4-thiadiazol-2-yl)acetamide; 1292-(Difluoromethyl)-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazole; 1302-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazole; 1312-[[6-[4-Chloro-3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole; 1322-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole; 1332-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole; 1342-[[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methoxy-1,3,4-thiadiazole; 1352-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole; 1362-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole; 1376-(4-Methyl-2-thienyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine; 1381-[(5-Methyl-3-pyridyl)methyl]-6-(4-methyl-2-thienyl)pyrazolo[4,3-b]pyridine;139 6-(5-Methyl-2-thienyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine;1405-[[6-(5-Chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile; 1416-(3-Chloro-2-thienyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine; 1425-[[6-[5-(Difluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile; 1431-((6-fluoropyridin-3-yl)methyl)-6-(5-(trifluoromethyl)thiophen-2-yl)-1H-pyrazolo[4,3-b]pyridine; 1445-[[6-[5-(Trifluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile; 1451-[(6-Fluoro-3-pyridyl)methyl]-6-(m-tolyl)pyrazolo[4,3-b]pyridine; 1461-[(5-Fluoro-3-pyridyl)methyl]-6-(m-tolyl)pyrazolo[4,3-b]pyridine; 1473-Fluoro-1-[(5-fluoro-3-pyridyl)methyl]-6-(m-tolyl)pyrazolo[4,3-b]pyridine;1486-(4-Chlorophenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;149 6-(4-Fluorophenyl)-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine; 1506-(4-Fluorophenyl)-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;1511-[[5-(Difluoromethoxy)-3-pyridyl]methyl]-6-(4-fluorophenyl)pyrazolo[4,3-b]pyridine; 1526-(3-Fluorophenyl)-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine; 1536-(2-Fluorophenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;154 6-(3-Methoxyphenyl)-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine; 1551-[(6-Fluoro-3-pyridyl)methyl]-6-(3-methoxyphenyl)pyrazolo[4,3-b]pyridine;1566-[3-(Difluoromethyl)phenyl]-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine;1575-[[6-[3-(Difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile; 1581-[(5-Chloro-3-pyridyl)methyl]-6-[3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 1596-[3-(Difluoromethoxy)phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 1606-[3-(1,1-Difluoroethyl)phenyl]-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 1616-[3-(1,1-Difluoroethyl)phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 1621-(2-Pyridylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;1631-(3-Pyridylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;1641-(4-Pyridylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;1651-[(6-Methyl-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 1661-[(2-Methyl-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 1671-[(5-Methyl-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 1681-[(4-Methyl-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 1691-[(6-Fluoro-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 1701-[(2-Fluoro-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 1711-[(5-Fluoro-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 1721-[(2-Methoxy-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 1731-[(5-Methoxy-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 174 6-[3-(Trifluoromethyl)phenyl]-1-[[6-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridine; 1756-[3-(Trifluoromethyl)phenyl]-1-[[5-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridine; 1766-[3-(Trifluoromethyl)phenyl]-1-[[4-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridine; 1776-(4-Fluoro-3-methyl-phenyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine;1783-Fluoro-6-(4-fluoro-3-methyl-phenyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine; 1796-(4-Fluoro-3-methyl-phenyl)-1-[(2-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 1806-(4-Fluoro-3-methyl-phenyl)-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 1816-(4-Fluoro-3-methyl-phenyl)-1-[(4-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 1826-(4-Fluoro-3-methyl-phenyl)-1-[(6-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 1836-(4-Fluoro-3-methyl-phenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 1846-(3,5-Difluorophenyl)-1-[(4-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;1856-(3,5-Difluorophenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;186 6-(3,4-Difluorophenyl)-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine;187 6-(3,4-Difluorophenyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine;1886-(3,4-Difluorophenyl)-1-[(2-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;1896-(3,4-Difluorophenyl)-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;1906-(3,4-Difluorophenyl)-1-[(4-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;1916-(3,4-Difluorophenyl)-1-[(6-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;1926-(3,4-Difluorophenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;193 6-(3,4-Difluorophenyl)-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 1941-[[5-(Difluoromethoxy)-3-pyridyl]methyl]-6-(3,4-difluorophenyl)pyrazolo[4,3-b]pyridine; 1956-(3-Chloro-4-fluoro-phenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 1966-(3-Chloro-4-fluoro-phenyl)-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 1976-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine; 1986-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine; 199 6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-methyl-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine; 2006-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2016-(3-(difluoromethyl)-4-fluorophenyl)-1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine; 2026-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2035-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile; 2046-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(6-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2056-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(6-methoxy-2-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2066-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(2-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2076-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2081-[(5-Chloro-3-pyridyl)methyl]-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine; 2096-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[[5-(difluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridine; 2101-[[5-(Difluoromethoxy)-3-pyridyl]methyl]-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine; 2116-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[[5-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridine; 2125-[[6-[3-(Difluoromethyl)-2-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile; 2131-[(5-Chloro-3-pyridyl)methyl]-6-[3-(difluoromethyl)-2-fluoro-phenyl]pyrazolo[4,3-b]pyridine; 2146-(3,4-Dichlorophenyl)-1-[(6-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;215 6-(3,4-Dichlorophenyl)-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2166-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine; 2176-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2186-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2195-[[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile; 2206-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2211-[(5-Chloro-3-pyridyl)methyl]-6-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine; 2226-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine; 2236-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine; 224 6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2256-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2265-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile; 2276-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(6-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2286-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(6-methoxy-2-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2296-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(2-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2306-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2311-[(5-Chloro-3-pyridyl)methyl]-6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine; 2326-[4-Chloro-3-(Difluoromethyl)phenyl]-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2331-[(5-Fluoro-3-pyridyl)methyl]-6-[4-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 2346-[4-Fluoro-3-(trifluoromethyl)phenyl]-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2356-(3-Bromo-4-fluorophenyl)-1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine; 2365-[[6-[4-Chloro-3-(1,1-difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile; 2376-[4-Chloro-3-(1,1-difluoroethyl)phenyl]-1-[(5-chloro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2386-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine; 239 6-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2406-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2415-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile; 2426-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2436-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(5-chloro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2446-(2,4-Difluoro-3-methyl-phenyl)-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine;2456-(2,4-Difluoro-3-methyl-phenyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine;2466-(2,4-Difluoro-3-methyl-phenyl)-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2476-(2,4-Difluoro-3-methyl-phenyl)-1-[(4-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2486-(2,4-Difluoro-3-methyl-phenyl)-1-[(6-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2496-(2,4-Difluoro-3-methyl-phenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2501-(2-Pyridylmethyl)-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine;2511-[(5-Fluoro-3-pyridyl)methyl]-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine; 2521-[(5-Methoxy-3-pyridyl)methyl]-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine; 253 1-[[5-(Difluoromethoxy)-3-pyridyl]methyl]-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine; 2541-(Pyridazin-4-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;255 6-(m-Tolyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine; 2566-(3-Fluorophenyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine; 2576-[3-(1,1-Difluoroethyl)phenyl]-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine; 2581-(Pyridazin-3-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;2596-(4-Fluoro-3-methyl-phenyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine;2606-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine; 2616-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine; 2626-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(6-methylpyridazin-3-yl)methyl]pyrazolo[4,3-b]pyridine; 2636-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine; 2646-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(6-methylpyridazin-3-yl)methyl]pyrazolo[4,3-b]pyridine; 2656-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine; 2666-(3,4-Difluorophenyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine;2676-(4-Chloro-3-methyl-phenyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine;2681-(Pyridazin-3-ylmethyl)-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine;2696-(2,4-Difluoro-3-methyl-phenyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine; 2706-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(pyrimidin-4-ylmethyl)pyrazolo[4,3-b]pyridine; 271 6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(pyrimidin-4-ylmethyl)pyrazolo[4,3-b]pyridine; 2726-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(pyrazin-2-ylmethyl)pyrazolo[4,3-b]pyridine; 2736-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(pyrazin-2-ylmethyl)pyrazolo[4,3-b]pyridine; 2746-[3-(1,1-Difluoroethyl)phenyl]-1-(pyrimidin-5-ylmethyl)pyrazolo[4,3-b]pyridine; 2756-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(pyrimidin-5-ylmethyl)pyrazolo[4,3-b]pyridine; 2761-(Pyrimidin-5-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;277 6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-(pyrimidin-5-ylmethyl)pyrazolo[4,3-b]pyridine; 2786-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(pyrimidin-5-ylmethyl)pyrazolo[4,3-b]pyridine; 2796-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(pyrimidin-5-ylmethyl)pyrazolo[4,3-b]pyridine; 2806-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(6-methylpyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine; 2816-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(6-methylpyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine; 2826-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(2-methylpyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine; 2831-[(2-Methylpyrimidin-4-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 2846-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(2-methylpyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine; 2856-(3,4-Difluorophenyl)-1-[(2-methylpyrimidin-5-yl)methyl]pyrazolo[4,3-b]pyridine; 286 6-(4-Chloro-3-methyl-phenyl)-1-[(2-methylpyrimidin-5-yl)methyl]pyrazolo[4,3-b]pyridine; 2871-[(5-Methylpyrimidin-2-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 2886-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(6-methoxypyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine; 2896-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(6-methoxypyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine; 2906-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(2-methoxypyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine; and 2916-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(2-methoxypyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine; 292(5-((6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)methanol; 2932-Fluoro-5-(1-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)benzoic acid; 2946-(3-(Difluoromethyl)-4-fluorophenyl)-1-((6-(fluoro-18F)pyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine; 2952-[[3-Bromo-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 2962-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; and 2972-[[3-Deuterio-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;and pharmaceutically acceptable salts, N-oxides, or solvates thereof.

A further embodiment of the current invention is a compound selectedfrom the group consisting of:

-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyri    din-1l-yl]methyl]-5-methyloxazole;-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyri    din-1l-yl]methyl]-5-methyl-1,3,4-oxadiazole;-   5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-isoxazole;-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;-   3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,2,4-oxadiazole;-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole;-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine;-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine;-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(pyrimidin-5-ylmethyl)pyrazolo[4,3-b]pyridine;    and pharmaceutically acceptable salts, N-oxides, or solvates    thereof.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising:

-   -   (A) an effective amount of at least one compound selected from        compounds of Formula (I)

-   -   wherein    -   R¹ is H, halo, or CH₃;    -   Ar¹ is selected from the group consisting of:        -   (a) phenyl substituted with one member selected from the            group consisting of: halo, C₁₋₆alkyl, OC₁₋₆alkyl,            C₁₋₆perhaloalkyl, and OC₁₋₆perhaloalkyl;        -   (b) phenyl substituted with two or three members each            independently selected from the group consisting of: halo,            C₁₋₆alkyl, C₁₋₆perhaloalkyl, OC₁₋₆perhaloalkyl, and CO₂H;            and        -   (c) thienyl substituted with a member selected from the            group consisting of: halo, C₁₋₆alkyl, and C₁₋₆perhaloalkyl;            and pyridine substituted with CF₃; and    -   R² is selected from the group consisting of:        -   (d)

-   -   -   wherein            -   R^(a) is halo, C₁₋₆alkyl or CN;            -   R^(b) is H or C₁₋₂alkyl;            -   R^(c) is selected from the group consisting of: H,                C₁₋₆alkyl, C₁₋₆perhaloalkyl, CH₂OH, OC₁₋₆alkyl, OH, NH₂,                NH(CH₃), N(CH₃)₂, NH(C═O)CH₃, cyclopropyl, and phenyl;            -   X¹ is NCH₃, S or O;            -   X² is O, NH or NCH₃;            -   X³ is O or S;            -   X⁴ is NH or O;            -   X⁵ is NCH₃ or O;            -   X⁶ is NCH₃ or S;            -   and n is 2;        -   (e) phenyl; phenyl substituted with one or two members            independently selected from the group consisting of: halo,            OC₁₋₆alkyl, C₁₋₆perhaloalkyl, and CN; and        -   (f)

-   -   -   wherein            -   R^(d) is H or OC₁₋₆alkyl;            -   R^(e) is a member selected from the group consisting of:                H, halo, C₁₋₆alkyl, C₁₋₆perhaloalkyl, OC₁₋₆alkyl,                OC₁₋₆perhaloalkyl, and CN; and            -   R^(f) is H, C₁₋₆alkyl or OC₁₋₆alkyl;                and pharmaceutically acceptable salts, stereoisomers,                isotopic variants, N-oxides or solvates of compounds of                Formula (I);

and (B) at least one pharmaceutically acceptable excipient.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising and effective amount of at least one compound ofFormula (IA), as well as pharmaceutically acceptable salts, N-oxides orsolvates of compounds of Formula (IA), pharmaceutically acceptableprodrugs of compounds of Formula (IA), and pharmaceutically activemetabolites of Formula (IA); and at least one pharmaceuticallyacceptable excipient.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising and effective amount of at least one compound ofFormula (IB), as well as pharmaceutically acceptable salts, N-oxides orsolvates of compounds of Formula (IB), pharmaceutically acceptableprodrugs of compounds of Formula (IB), and pharmaceutically activemetabolites of Formula (IB); and at least one pharmaceuticallyacceptable excipient.

An additional embodiment of the invention is a pharmaceuticalcomposition comprising and effective amount of at least one compound inTable 1, as well as pharmaceutically acceptable salts, N-oxides orsolvates of compounds of Table 1, pharmaceutically acceptable prodrugsof compounds of Table 1, and pharmaceutically active metabolites ofTable 1; and at least one pharmaceutically acceptable excipient.

Also within the scope of the invention are enantiomers and diastereomersof the compounds of Formula (I) (as well as Formulas (IA), and (IB)).Also within the scope of the invention are the pharmaceuticallyacceptable salts, N-oxides or solvates of the compounds of Formula (I)(as well as Formulas (IA), and (IB)). Also within the scope of theinvention are the pharmaceutically acceptable prodrugs of compounds ofFormula (I) (as well as Formulas (IA), and (IB)), and pharmaceuticallyactive metabolites of the compounds of Formula (I) (as well as Formulas(IA), and (IB)).

Also within the scope of the invention are isotopic variations ofcompounds of Formula (I) (as well as Formulas (IA), and (IB)), such as,e.g., deuterated compounds of Formula (I). Also within the scope of theinvention are the pharmaceutically acceptable salts, N-oxides orsolvates of the isotopic variations of the compounds of Formula (I) (aswell as Formulas (IA), and (IB)). Also within the scope of the inventionare the pharmaceutically acceptable prodrugs of the isotopic variationsof the compounds of Formula (I) (as well as Formulas (IA), and (IB)),and pharmaceutically active metabolites of the isotopic variations ofthe compounds of Formula (I) (as well as Formulas (IA), and (IB)).

An additional embodiment of the invention is a method of treating asubject suffering from or diagnosed with a disease, disorder, or medicalcondition mediated by GluN2B receptor activity, comprising administeringto a subject in need of such treatment an effective amount of at leastone compound selected from compounds of Formula (I):

wherein

R¹ is H, halo, or CH₃;

Ar¹ is selected from the group consisting of:

-   -   (a) phenyl substituted with one member selected from the group        consisting of: halo, C₁₋₆alkyl, OC₁₋₆alkyl, C₁₋₆perhaloalkyl,        and OC₁₋₆perhaloalkyl;    -   (b) phenyl substituted with two or three members each        independently selected from the group consisting of: halo,        C₁₋₆alkyl, C₁₋₆perhaloalkyl, OC₁₋₆perhaloalkyl, and CO₂H; and    -   (c) thienyl substituted with a member selected from the group        consisting of: halo, C₁₋₆alkyl, and C₁₋₆perhaloalkyl; and        pyridine substituted with CF₃; and

R² is selected from the group consisting of:

-   -   (d)

-   -   wherein        -   R^(a) is halo, C₁₋₆alkyl or CN;        -   R^(b) is H or C₁₋₂alkyl;        -   R^(c) is selected from the group consisting of: H,            C₁₋₆alkyl, C₁₋₆perhaloalkyl, CH₂OH, OC₁₋₆alkyl, OH, NH₂,            NH(CH₃), N(CH₃)₂, NH(C═O)CH₃, cyclopropyl, and phenyl;        -   X¹ is NCH₃, S or O;        -   X² is O, NH or NCH₃;        -   X³ is O or S;        -   X⁴ is NH or O;        -   X⁵ is NCH₃ or O;        -   X⁶ is NCH₃ or S;        -   and n is 2;    -   (e) phenyl; phenyl substituted with one or two members        independently selected from the group consisting of: halo,        OC₁₋₆alkyl, C₁₋₆perhaloalkyl, and CN; and    -   (f)

-   -   wherein        -   R^(d) is H or OC₁₋₆alkyl;        -   R^(e) is a member selected from the group consisting of: H,            halo, C₁₋₆alkyl,        -   C₁₋₆perhaloalkyl, OC₁₋₆alkyl, OC₁₋₆perhaloalkyl, and CN; and        -   R^(f) is H, C₁₋₆alkyl or OC₁₋₆alkyl;            and pharmaceutically acceptable salts, stereoisomers,            isotopic variants, N-oxides, or solvates thereof, to a            subject in need thereof.

An additional embodiment of the invention is a method of treating asubject suffering from or diagnosed with a disease, disorder, or medicalcondition mediated by GluN2B receptor activity, comprising administeringto a subject in need of such treatment an effective amount of at leastone compound selected from compounds of Formula (I) (as well as Formulas(IA), and (IB)), enantiomers and diastereomers of the compounds ofFormula (I), isotopic variations of the compounds of Formula (I), andpharmaceutically acceptable salts of all of the foregoing.

In preferred embodiments of the inventive method, the disease, disorder,or medical condition is selected from: neurologic and psychiatricdisorders including, but not limited to: (1) mood disorders and moodaffective disorders; (2) neurotic, stress-related and somatoformdisorders including anxiety disorders; (3) disorders of psychologicaldevelopment; (4) behavioral syndromes associated with physiologicaldisturbances and physical factors; (5) extrapyramidal and movementdisorders; (6) episodic and paroxysmal disorders, epilepsy; (7) pain;(8) forms of neurodegeneration; (9) cerebrovascular diseases, acute andchronic; and any sequelae of cerebrovascular diseases.

Examples of mood disorders and mood affective disorders that can betreated according to the present invention include, but are not limitedto, bipolar disorder I depressed, hypomanic, manic and mixed form;bipolar disorder II; depressive disorders, such as single depressiveepisode or recurrent major depressive disorder, minor depressivedisorder, treatment-resistant depression, depressive disorder withpostpartum onset, depressive disorders with psychotic symptoms;persistent mood disorders, such as cyclothymia, dysthymia, euthymia; andpremenstrual dysphoric disorder.

Examples of disorders belonging to the neurotic, stress-related andsomatoform disorders that can be treated according to the presentinvention include, but are not limited to, anxiety disorders, generalanxiety disorder, panic disorder with or without agoraphobia, specificphobia, social anxiety disorder, chronic anxiety disorders; obsessivecompulsive disorder; reaction to sever stress and adjustment disorders,such as post-traumatic stress disorder (PTSD); other neurotic disorderssuch as depersonalisation-derealisation syndrome.

Examples of disorders of psychological development that can be treatedaccording to the present invention include, but are not limited topervasive developmental disorders, including but not limited toAsperger's syndrome and Rett's syndrome, autistic disorders, childhoodautism and overactive disorder associated with mental retardation andstereotyped movements, specific developmental disorder of motorfunction, specific developmental disorders of scholastic skills.

Examples of behavioral syndromes associated with physiologicaldisturbances and physical factors according to the present inventioninclude but are not limited to mental and behavioral disordersassociated with childbirth, including but not limited to postnatal(postpartum) and prenatal depression; eating disorders, including butnot limited to anorexia nervosa, bulimia nervosa, pica and binge eatingdisorder.

Examples of extrapyramidal and movement disorders that can be treatedaccording to the present invention include, but are not limited toParkinson's disease; second Parkinsonism, such as post encephaliticParkinsonism; Parkinsonism comprised in other disorders; Lewis bodydisease; degenerative diseases of the basal ganglia; otherextrapyramidal and movement disorders including but not limited totremor, essential tremor and drug-induced tremor, myoclonus, chorea anddrug-induced chorea, drug-induced tics and tics of organic origin,drug-induced acute dystonia, drug-induced tardive dyskinesia,L-dopa-induced dyskinesia; neuroleptic-induced movement disordersincluding but not limited to neuroleptic malignant syndrome (NMS),neuroleptic induced parkinsonism, neuroleptic-induced early onset oracute dyskinesia, neuroleptic-induced acute dystonia,neuroleptic-induced acute akathisia, neuroleptic-induced tardivedyskinesia, neuroleptic-induced tremor; restless leg syndrome, Stiff-mansyndrome.

Further examples of movement disorders with malfunction and/ordegeneration of basal ganglia that can be treated according to thepresent invention include but are not limited to dystonia including butnot limited to focal dystonia, multiple-focal or segmental dystonia,torsion dystonia, hemispheric, generalised and tardive dystonia (inducedby psychopharmacological drugs). Focal dystonia includes cervicaldystonia (torticolli), blepharospasm (cramp of the eyelid), appendiculardystonia (cramp in the extremities, like the writer's cramp),oromandibular dystonia and spasmodic dysphonia (cramp of the vocalcord);

Examples for episodic and paroxysmal disorders that can be treatedaccording to the present invention include, but are not limited toepilepsy, including localization-related (focal)(partial) idiopathicepilepsy and epileptic syndromes with seizures of localized onset,localization-related (focal)(partial) symptomatic epilepsy and epilepticsyndromes with simple partial seizures, localization-related(focal)(partial) symptomatic epilepsy and epileptic syndromes withcomplex partial seizures, generalized idiopathic epilepsy and epilepticsyndromes including but not limited to myoclonic epilepsy in infancy,neonatal convulsions (familial), childhood absence epilepsy(pyknolepsy), epilepsy with grand mal seizures on awakening, absenceepilepsy, myoclonic epilepsy (impulsive petit mal) and nonspecificatonic, clonic, myoclonic, tonic, tonic-clonic epileptic seizures.

Further examples of epilepsy that can be treated according to thepresent invention include, but are not limited to epilepsy withmyoclonic absences, myoclonic-astatic seizures, infantile spasms,Lennox-Gastaut syndrome, Salaam attacks, symptomatic early myoclonicencephalopathy, West's syndrome, petit and grand mal seizures; statusepilepticus.

Examples of pain include, but are not limited to pain disorders relatedto psychological factors, such as persistent somatoform disorders;acute, chronic and chronic intractable pain, headache; acute and chronicpain related to physiological processes and physical disorders includingbut not limited to back pain, tooth pain, abdominal pain, low back pain,pain in joints; acute and chronic pain that is related to diseases ofthe musculoskeletal system and connective tissue including, but notlimited to rheumatism, myalgia, neuralgia and fibromyalgia; acute andchronic pain that is related to nerve, nerve root and plexus disorders,such as trigeminal pain, postzoster neuralgia, phantom limb syndromewith pain, carpal tunnel syndrome, lesion of sciatic nerve, diabeticmononeuropathy; acute and chronic pain that is related topolyneuropathies and other disorders of the peripheral nervous system,such as hereditary and idiopathic neuropathy, inflammatorypolyneuropathy, polyneuropathy induced by drugs, alcohol or toxicagents, polyneuropathy in neoplastic disease, diabetic polyneuropathy.

Examples of diseases that include forms of neurodegeneration include,but are not limited to, acute neurodegeneration, such as intracranialbrain injuries, such as stroke, diffuse and local brain injuries,epidural, subdural and subarachnoid haemorrhage, and chronicneurodegeneration, such as Alzheimer's disease, Huntington's disease,multiple sclerosis and ALS.

Examples of cerebrovascular diseases include, but are not limited to,subarachnoid haemorrhage, intracerebral haemorrhage and othernontraumatic intracranial haemorrhage, cerebral infarction, stroke,occlusion and stenosis or precerebral and cerebral arteries, notresulting in cerebral infarction, dissection of cerebral arteries,cerebral aneurysm, cerebral atherosclerosis, progressive vascularleukoencephalopathy, hypertensive encephalopathy, nonpyogenic thrombosisof intracranial venous system, cerebral arteritis, cerebral amyloidangiopathy and sequelae of cerebrovascular diseases.

In some embodiments, administration of a compound of the invention, orpharmaceutically acceptable salt thereof, is effective in preventing thedisease; for example, preventing a disease, condition or disorder in anindividual who may be predisposed to the disease, condition or disorderbut does not yet experience or display the pathology or symptomatologyof the disease.

Additional embodiments, features, and advantages of the invention willbe apparent from the following detailed description and through practiceof the invention.

The invention may be more fully appreciated by reference to thefollowing description, including the following glossary of terms and theconcluding examples. For the sake of brevity, the disclosures of thepublications, including patents, cited in this specification are hereinincorporated by reference.

As used herein, the terms “including”, “containing” and “comprising” areused herein in their open, non-limiting sense.

The term “alkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude methyl (Me, which also may be structurally depicted by thesymbol, “/”), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl,isohexyl, and groups that in light of the ordinary skill in the art andthe teachings provided herein would be considered equivalent to any oneof the foregoing examples. The term C₁₋₄alkyl as used here refers to astraight- or branched-chain alkyl group having from 1 to 4 carbon atomsin the chain. The term C₁₋₆alkyl as used here refers to a straight- orbranched-chain alkyl group having from 1 to 6 carbon atoms in the chain.

The term “aryl” refers to a monocyclic, aromatic carbocycle (ringstructure having ring atoms that are all carbon) having 6 atoms perring. (Carbon atoms in the aryl groups are sp² hybridized.)

The term “phenyl” represents the following moiety:

The term “thienyl” represents the following moiety:

The term “heteroaryl” refers to a monocyclic or fused bicyclicheterocycle (ring structure having ring atoms selected from carbon atomsand up to four heteroatoms selected from nitrogen, oxygen, and sulfur)having from 3 to 9 ring atoms per heterocycle. Illustrative examples ofheteroaryl groups include the following entities, in the form ofproperly bonded moieties:

Those skilled in the art will recognize that the species of heteroaryl,cycloalkyl, aryl and heterocycloalkyl groups listed or illustrated aboveare not exhaustive, and that additional species within the scope ofthese defined terms may also be selected.

The term “cyano” refers to the group —CN.

The term “cycloalkyl” refers to a saturated or partially saturated,monocyclic, fused polycyclic, or spiro polycyclic carbocycle having from3 to 12 ring atoms per carbocycle. Illustrative examples of cycloalkylgroups include the following entities, in the form of properly bondedmoieties:

The term “halo” represents chloro, fluoro, bromo or iodo.

The term “perhaloalkyl” or “haloalkyl” refers to a straight- orbranched-chain alkyl group having from 1 to 6 carbon atoms in the chainoptionally substituting hydrogens with halogens. The term“C₁₋₄haloalkyl” as used here refers to a straight- or branched-chainalkyl group having from 1 to 4 carbon atoms in the chain, optionallysubstituting hydrogens with halogens. The term “C₁₋₆haloalkyl” as usedhere refers to a straight- or branched-chain alkyl group having from 1to 6 carbon atoms in the chain, optionally substituting hydrogens withhalogens. Examples of “perhaloalkyl”, “haloalkyl” groups includetrifluoromethyl (CF₃), difluoromethyl (CF₂H), monofluoromethyl (CH₂F),pentafluoroethyl (CF₂CF₃), tetrafluoroethyl (CHFCF₃), monofluoroethyl(CH₂CH₂F), trifluoroethyl (CH₂CF₃), tetrafluorotrifluoromethylethyl(—CF(CF₃)₂), and groups that in light of the ordinary skill in the artand the teachings provided herein would be considered equivalent to anyone of the foregoing examples.

The term “perhaloalkoxy” or “haloalkoxy” refers to a straight- orbranched-chain alkoxy group having from 1 to 6 carbon atoms in the chainoptionally substituting hydrogens with halogens. Examples ofperhaloalkoxy groups include trifluoromethoxy (OCF₃), difluoromethoxy(OCF₂H), monofluoromethoxy (OCH₂F), monofluoroethoxy (OCH₂CH₂F),pentafluoroethoxy (OCF₂CF₃), tetrafluoroethoxy (OCHFCF₃),trifluoroethoxy (OCH₂CF₃), tetrafluorotrifluoromethylethoxy(—OCF(CF₃)₂), and groups that in light of the ordinary skill in the artand the teachings provided herein would be considered equivalent to anyone of the foregoing examples.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system. In cases where a specifiedmoiety or group is not expressly noted as being optionally substitutedor substituted with any specified substituent, it is understood thatsuch a moiety or group is intended to be unsubstituted.

The terms “para”, “meta”, and “ortho” have the meanings as understood inthe art. Thus, for example, a fully substituted phenyl group hassubstituents at both “ortho”(o) positions adjacent to the point ofattachment of the phenyl ring, both “meta” (m) positions, and the one“para” (p) position across from the point of attachment. To furtherclarify the position of substituents on the phenyl ring, the 2 differentortho positions will be designated as ortho and ortho′ and the 2different meta positions as meta and meta′ as illustrated below.

When referring to substituents on a pyridyl group, the terms “para”,“meta”, and “ortho” refer to the placement of a substituent relative tothe point of attachment of the pyridyl ring. For example, the structurebelow is described as 3-pyridyl with the X¹ substituent in the orthoposition, the X² substituent in the meta position, and X³ substituent inthe para position:

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity that could be obtained under the particular stoichiometricconditions. Concentrations that are given as percentages refer to massratios, unless indicated differently.

The terms “buffered” solution or “buffer” solution are used hereininterchangeably according to their standard meaning. Buffered solutionsare used to control the pH of a medium, and their choice, use, andfunction is known to those of ordinary skill in the art. See, forexample, G. D. Considine, ed., Van Nostrand's Encyclopedia of Chemistry,p. 261, 5^(th) ed. (2005), describing, inter alia, buffer solutions andhow the concentrations of the buffer constituents relate to the pH ofthe buffer. For example, a buffered solution is obtained by adding MgSO₄and NaHCO₃ to a solution in a 10:1 w/w ratio to maintain the pH of thesolution at about 7.5.

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers of the compounds of the generalformula, and mixtures thereof, are considered within the scope of theformula. Thus, any formula given herein is intended to represent aracemate, one or more enantiomeric forms, one or more diastereomericforms, one or more atropisomeric forms, and mixtures thereof.Furthermore, certain structures may exist as geometric isomers (i.e.,cis and trans isomers), as tautomers, or as atropisomers.

It is also to be understood that compounds that have the same molecularformula but differ in the nature or sequence of bonding of their atomsor the arrangement of their atoms in space are termed “isomers.” Isomersthat differ in the arrangement of their atoms in space are termed “.”

Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers.” When a compound has an asymmetriccenter, for example, it is bonded to four different groups, and a pairof enantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+)- or (−)-isomersrespectively). A chiral compound can exist as either an individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture.”

“Tautomers” refer to compounds that are interchangeable forms of aparticular compound structure, and that vary in the displacement ofhydrogen atoms and electrons. Thus, two structures may be in equilibriumthrough the movement of 7 electrons and an atom (usually H). Forexample, enols and ketones are tautomers because they are rapidlyinterconverted by treatment with either acid or base. Another example oftautomerism is the aci- and nitro-forms of phenyl nitromethane, that arelikewise formed by treatment with acid or base.

Tautomeric forms may be relevant to the attainment of the optimalchemical reactivity and biological activity of a compound of interest.

The compounds of this invention may possess one or more asymmetriccenters; such compounds can therefore be produced as individual (R)- or(S)-stereoisomers or as mixtures thereof.

Unless indicated otherwise, the description or naming of a particularcompound in the specification and claims is intended to include bothindividual enantiomers and mixtures, racemic or otherwise, thereof. Themethods for the determination of stereochemistry and the separation ofstereoisomers are well-known in the art.

Certain examples contain chemical structures that are depicted as anabsolute enantiomer but are intended to indicate enantiopure materialthat is of unknown configuration. In these cases (R*) or (S*) is used inthe name to indicate that the absolute stereochemistry of thecorresponding stereocenter is unknown. Thus, a compound designated as(R*) refers to an enantiopure compound with an absolute configuration ofeither (R) or (S). In cases where the absolute stereochemistry has beenconfirmed, the structures are named using (R) and (S).

The symbols

and

are used as meaning the same spatial arrangement in chemical structuresshown herein. Analogously, the symbols

and

are used as meaning the same spatial arrangement in chemical structuresshown herein.

Additionally, any formula given herein is intended to refer also tohydrates, solvates, and polymorphs of such compounds, and mixturesthereof, even if such forms are not listed explicitly. Certain compoundsof Formula (I) (as well as Formulas (IA), and (IB)), or pharmaceuticallyacceptable salts of compounds of Formula (I) (as well as Formulas (IA),and (IB)) may be obtained as solvates. Solvates include those formedfrom the interaction or complexation of compounds of the invention withone or more solvents, either in solution or as a solid or crystallineform. In some embodiments, the solvent is water and the solvates arehydrates. In addition, certain crystalline forms of compounds of Formula(I) ((as well as Formulas (IA), and (IB)) or pharmaceutically acceptablesalts of compounds of Formula (I) (as well as Formulas (IA), and (IB))may be obtained as co-crystals. In certain embodiments of the invention,compounds of Formula (I) were obtained in a crystalline form. In otherembodiments, crystalline forms of compounds of Formula (I) were cubic innature. In other embodiments, pharmaceutically acceptable salts ofcompounds of Formula (I) were obtained in a crystalline form. In stillother embodiments, compounds of Formula (I) were obtained in one ofseveral polymorphic forms, as a mixture of crystalline forms, as apolymorphic form, or as an amorphous form. In other embodiments,compounds of Formula (I) convert in solution between one or morecrystalline forms and/or polymorphic forms.

Reference to a compound herein stands for a reference to any one of: (a)the actually recited form of such compound, and (b) any of the forms ofsuch compound in the medium in which the compound is being consideredwhen named. For example, reference herein to a compound such as R—COOH,encompasses reference to any one of, for example, R—COOH_((s)),R—COOH_((sol)), and R—COO⁻ _((sol)). In this example, R—COOH_((s))refers to the solid compound, as it could be for example in a tablet orsome other solid pharmaceutical composition or preparation;R—COOH_((sol)) refers to the undissociated form of the compound in asolvent; and R—COO⁻ _((sol)) refers to the dissociated form of thecompound in a solvent, such as the dissociated form of the compound inan aqueous environment, whether such dissociated form derives fromR—COOH, from a salt thereof, or from any other entity that yields R—COO—upon dissociation in the medium being considered. In another example, anexpression such as “exposing an entity to compound of formula R—COOH”refers to the exposure of such entity to the form, or forms, of thecompound R—COOH that exists, or exist, in the medium in which suchexposure takes place. In still another example, an expression such as“reacting an entity with a compound of formula R—COOH” refers to thereacting of (a) such entity in the chemically relevant form, or forms,of such entity that exists, or exist, in the medium in which suchreacting takes place, with (b) the chemically relevant form, or forms,of the compound R—COOH that exists, or exist, in the medium in whichsuch reacting takes place. In this regard, if such entity is for examplein an aqueous environment, it is understood that the compound R—COOH isin such same medium, and therefore the entity is being exposed tospecies such as R—COOH_((aq)) and/or R—COO⁻ _((aq)), where the subscript“(aq)” stands for “aqueous” according to its conventional meaning inchemistry and biochemistry. A carboxylic acid functional group has beenchosen in these nomenclature examples; this choice is not intended,however, as a limitation but it is merely an illustration. It isunderstood that analogous examples can be provided in terms of otherfunctional groups, including but not limited to hydroxyl, basic nitrogenmembers, such as those in amines, and any other group that interacts ortransforms according to known manners in the medium that contains thecompound. Such interactions and transformations include, but are notlimited to, dissociation, association, tautomerism, solvolysis,including hydrolysis, solvation, including hydration, protonation, anddeprotonation. No further examples in this regard are provided hereinbecause these interactions and transformations in a given medium areknown by any one of ordinary skill in the art.

In another example, a zwitterionic compound is encompassed herein byreferring to a compound that is known to form a zwitterion, even if itis not explicitly named in its zwitterionic form. Terms such aszwitterion, zwitterions, and their synonyms zwitterionic compound(s) arestandard IUPAC-endorsed names that are well known and part of standardsets of defined scientific names. In this regard, the name zwitterion isassigned the name identification CHEBI:27369 by the Chemical Entities ofBiological Interest (ChEBI) dictionary of molecular entities. Asgenerally well known, a zwitterion or zwitterionic compound is a neutralcompound that has formal unit charges of opposite sign. Sometimes thesecompounds are referred to by the term “inner salts”. Other sources referto these compounds as “dipolar ions”, although the latter term isregarded by still other sources as a misnomer. As a specific example,aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH,and it exists in some media (in this case in neutral media) in the formof the zwitterion ⁺H₃NCH₂COO⁻. Zwitterions, zwitterionic compounds,inner salts and dipolar ions in the known and well-established meaningsof these terms are within the scope of this invention, as would in anycase be so appreciated by those of ordinary skill in the art. Becausethere is no need to name each and every embodiment that would berecognized by those of ordinary skill in the art, no structures of thezwitterionic compounds that are associated with the compounds of thisinvention are given explicitly herein. They are, however, part of theembodiments of this invention. No further examples in this regard areprovided herein because the interactions and transformations in a givenmedium that lead to the various forms of a given compound are known byany one of ordinary skill in the art.

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine,chlorine, and iodine such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P,³²P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²⁵I, respectively. Such isotopically labeledcompounds are useful in metabolic studies (preferably with ¹⁴C),reaction kinetic studies (with, for example deuterium (i.e., D or ²H);or tritium (i.e., T or ³H)), detection or imaging techniques [such aspositron emission tomography (PET) or single-photon emission computedtomography (SPECT)] including drug or substrate tissue distributionassays, or in radioactive treatment of patients. In particular, an ¹⁸For ¹¹C labeled compound may be particularly preferred for PET or SPECTstudies. Further, substitution with heavier isotopes such as deuterium(i.e., ²H) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements. Isotopically labeled compounds of thisinvention and prodrugs thereof can generally be prepared by carrying outthe procedures disclosed in the schemes or in the examples andpreparations described below by substituting a readily availableisotopically labeled reagent for a non-isotopically labeled reagent.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of the species for the same variableelsewhere in the formula, unless stated otherwise.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ and S² _(example) isS₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ andS² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂, and S² _(example) is one of S₃ and S₄”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R,R¹, Ar¹, R², R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), HAL, X¹,X², X³, X⁴, X⁵, X⁶, L, n, het, and ring A, and any other genericsubstituent symbol used herein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂, and S₃, this listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂, and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R,R¹, Ar¹, R², R^(a), R^(b), R^(c), R^(d), R^(e), R^(f), R^(g), HAL, X¹,X², X³, X⁴, X⁵, X⁶, L, n, het, and ring A, and any other genericsubstituent symbol used herein.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁₋₄ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), embodimentsthat have three carbon members (C₃), and embodiments that have fourcarbon members (C₄).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with a total number N of carbon members in the chain thatsatisfies n≤N≤m, with m>n. Any disubstituent referred to herein is meantto encompass the various attachment possibilities when more than one ofsuch possibilities are allowed. For example, reference to disubstituent-A-B—, where A≠B, refers herein to such disubstituent with A attached toa first substituted member and B attached to a second substitutedmember, and it also refers to such disubstituent with A attached to thesecond substituted member and B attached to the first substitutedmember.

The invention includes also pharmaceutically acceptable salts of thecompounds of Formula (I) (as well as Formulas (IA), and (IB)),preferably of those described above and of the specific compoundsexemplified herein, and methods of treatment using such salts.

The term “pharmaceutically acceptable” means approved or approvable by aregulatory agency of Federal or a state government or the correspondingagency in countries other than the United States, or that is listed inthe U. S. Pharmacopoeia or other generally recognized pharmacopoeia foruse in animals, and more particularly, in humans.

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of compounds represented by Formula (I) (as well asFormulas (IA), and (IB)) that are non-toxic, biologically tolerable, orotherwise biologically suitable for administration to the subject. Itshould possess the desired pharmacological activity of the parentcompound. See, generally, G. S. Paulekuhn, et al., “Trends in ActivePharmaceutical Ingredient Salt Selection based on Analysis of the OrangeBook Database”, J. Med. Chem., 2007, 50:6665-72, S. M. Berge, et al.,“Pharmaceutical Salts”, J Pharm Sci., 1977, 66:1-19, and Handbook ofPharmaceutical Salts, Properties, Selection, and Use, Stahl and Wermuth,Eds., Wiley-VCH and VHCA, Zurich, 2002. Examples of pharmaceuticallyacceptable salts are those that are pharmacologically effective andsuitable for contact with the tissues of patients without unduetoxicity, irritation, or allergic response. A compound of Formula (I)(as well as Formulas (IA), and (IB)) may possess a sufficiently acidicgroup, a sufficiently basic group, or both types of functional groups,and accordingly react with a number of inorganic or organic bases, andinorganic and organic acids, to form a pharmaceutically acceptable salt.

Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, propionates,decanoates, caprylates, acrylates, formates, isobutyrates, caproates,heptanoates, propiolates, oxalates, malonates, succinates, suberates,sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates,benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates,hydroxybenzoates, methoxybenzoates, phthalates, sulfonates,xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates,citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates,methane-sulfonates, propanesulfonates, naphthalene-1-sulfonates,naphthalene-2-sulfonates, and mandelates.

When the compounds of Formula (I) (as well as Formulas (IA), and (IB))contain a basic nitrogen, the desired pharmaceutically acceptable saltmay be prepared by any suitable method available in the art. Forexample, treatment of the free base with an inorganic acid, such ashydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid,nitric acid, boric acid, phosphoric acid, and the like, or with anorganic acid, such as acetic acid, phenylacetic acid, propionic acid,stearic acid, lactic acid, ascorbic acid, maleic acid, hydroxymaleicacid, isethionic acid, succinic acid, valeric acid, fumaric acid,malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid,oleic acid, palmitic acid, lauric acid, a pyranosidyl acid, such asglucuronic acid or galacturonic acid, an alpha-hydroxy acid, such asmandelic acid, citric acid, or tartaric acid, an amino acid, such asaspartic acid, glutaric acid or glutamic acid, an aromatic acid, such asbenzoic acid, 2-acetoxybenzoic acid, naphthoic acid, or cinnamic acid, asulfonic acid, such as laurylsulfonic acid, p-toluenesulfonic acid,methanesulfonic acid, ethanesulfonic acid, any compatible mixture ofacids such as those given as examples herein, and any other acid andmixture thereof that are regarded as equivalents or acceptablesubstitutes in light of the ordinary level of skill in this technology.

When the compound of Formula (I) (as well as Formulas (IA), and (IB)) isan acid, such as a carboxylic acid or sulfonic acid, the desiredpharmaceutically acceptable salt may be prepared by any suitable method,for example, treatment of the free acid with an inorganic or organicbase, such as an amine (primary, secondary or tertiary), an alkali metalhydroxide, alkaline earth metal hydroxide, any compatible mixture ofbases such as those given as examples herein, and any other base andmixture thereof that are regarded as equivalents or acceptablesubstitutes in light of the ordinary level of skill in this technology.Illustrative examples of suitable salts include organic salts derivedfrom amino acids, such as N-methyl-D-glucamine, lysine, choline, glycineand arginine, ammonia, carbonates, bicarbonates, primary, secondary, andtertiary amines, and cyclic amines, such as tromethamine, benzylamines,pyrrolidines, piperidine, morpholine, and piperazine, and inorganicsalts derived from sodium, calcium, potassium, magnesium, manganese,iron, copper, zinc, aluminum, and lithium.

The invention also relates to pharmaceutically acceptable prodrugs ofthe compounds of Formula (I) (as well as Formulas (IA), and (IB)), andtreatment methods employing such pharmaceutically acceptable prodrugs.The term “prodrug” means a precursor of a designated compound that,following administration to a subject, yields the compound in vivo via achemical or physiological process such as solvolysis or enzymaticcleavage, or under physiological conditions (e.g., a prodrug on beingbrought to physiological pH is converted to the compound of Formula (I).A “pharmaceutically acceptable prodrug” is a prodrug that is non-toxic,biologically tolerable, and otherwise biologically suitable foradministration to the subject. Illustrative procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Exemplary prodrugs include compounds having an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxyl, or carboxylic acid group of a compound of Formula (I)(as well as Formulas (IA), and (IB)). Examples of amino acid residuesinclude the twenty naturally occurring amino acids, commonly designatedby three letter symbols, as well as 4-hydroxyproline, hydroxylysine,demosine, isodemosine, 3-methylhistidine, norvalin, beta-alanine,gamma-aminobutyric acid, citrulline homocysteine, homoserine, ornithineand methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) (as wellas Formulas (IA), and (IB)) as amides or alkyl esters. Examples ofamides include those derived from ammonia, primary C₁₋₆alkyl amines andsecondary di(C₁₋₆alkyl) amines. Secondary amines include 5- or6-membered heterocycloalkyl or heteroaryl ring moieties. Examples ofamides include those that are derived from ammonia, C₁₋₃alkyl primaryamines, and di(C₁₋₂alkyl)amines. Examples of esters of the inventioninclude C₁₋₇alkyl, C₅₋₇cycloalkyl, phenyl, and phenyl(C₁₋₆alkyl) esters.Preferred esters include methyl esters. Prodrugs may also be prepared byderivatizing free hydroxy groups using groups including hemisuccinates,phosphate esters, dimethylaminoacetates, andphosphoryloxymethyloxycarbonyls, following procedures such as thoseoutlined in Fleisher et al., Adv. Drug Delivery Rev. 1996, 19, 115-130.Carbamate derivatives of hydroxy and amino groups may also yieldprodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters ofhydroxy groups may also provide prodrugs. Derivatization of hydroxygroups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acylgroup may be an alkyl ester, optionally substituted with one or moreether, amine, or carboxylic acid functionalities, or where the acylgroup is an amino acid ester as described above, is also useful to yieldprodrugs. Prodrugs of this type may be prepared as described in Robinsonet al., J Med Chem. 1996, 39 (1), 10-18. Free amines can also bederivatized as amides, sulfonamides or phosphonamides. All of theseprodrug moieties may incorporate groups including ether, amine, andcarboxylic acid functionalities.

The present invention also relates to pharmaceutically activemetabolites of the compounds of Formula (I) (as well as Formulas (IA),and (IB)), which may also be used in the methods of the invention. A“pharmaceutically active metabolite” means a pharmacologically activeproduct of metabolism in the body of a compound of Formula (I) (as wellas Formulas (IA), and (IB)) as applicable) or salt thereof. Prodrugs andactive metabolites of a compound may be determined using routinetechniques known or available in the art. See, e.g., Bertolini, et al.,J Med Chem. 1997, 40, 2011-2016; Shan, et al., J Pharm Sci. 1997, 86(7), 765-767; Bagshawe, Drug Dev Res. 1995, 34, 220-230; Bodor, Adv DrugRes. 1984, 13, 224-331; Bundgaard, Design of Prodrugs (Elsevier Press,1985); and Larsen, Design and Application of Prodrugs, Drug Design andDevelopment (Krogsgaard-Larsen, et al., eds., Harwood AcademicPublishers, 1991).

The compounds of Formula (I) (as well as Formulas (IA), and (IB)) andtheir pharmaceutically acceptable salts, pharmaceutically acceptableprodrugs, and pharmaceutically active metabolites of the presentinvention are useful as modulators of the GluN2B receptor in the methodsof the invention. As such modulators, the compounds may act asantagonists, agonists, or inverse agonists. The term “modulators”include both inhibitors and activators, where “inhibitors” refer tocompounds that decrease, prevent, inactivate, desensitize, ordown-regulate the GluN2B receptor expression or activity, and“activators” are compounds that increase, activate, facilitate,sensitize, or up-regulate GluN2B receptor expression or activity.

The term “treat”, “treatment” or “treating”, as used herein, is intendedto refer to administration of an active agent or composition of theinvention to a subject for the purpose of affecting a therapeutic orprophylactic benefit through modulation of GluN2B receptor activity.Treating includes reversing, ameliorating, alleviating, inhibiting theprogress of, lessening the severity of, or preventing a disease,disorder, or condition, or one or more symptoms of such disease,disorder or condition mediated through modulation of GluN2B receptoractivity. The term “subject” refers to a mammalian patient in need ofsuch treatment, such as a human.

Accordingly, the invention relates to methods of using the compoundsdescribed herein to treat subjects diagnosed with or suffering from adisease, disorder, or condition mediated by GluN2B receptor activity,such as: bipolar disorder I depressed, hypomanic, manic and mixed form;bipolar disorder II; depressive disorders, such as single depressiveepisode or recurrent major depressive disorder, minor depressivedisorder, treatment-resistant depression, depressive disorder withpostpartum onset, disruptive mood dysregulation disorder, depressivedisorders with psychotic symptoms; persistent mood disorders, such ascyclothymia, dysthymia, euthymia; and premenstrual dysphoric disorder;anxiety disorders, general anxiety disorder, panic disorder with orwithout agoraphobia, specific phobia, social anxiety disorder, chronicanxiety disorders; obsessive compulsive disorder; reaction to severstress and adjustment disorders, such as post-traumatic stress disorder(PTSD); other neurotic disorders such as depersonalisation-derealisationsyndrome; pervasive developmental disorders, including but not limitedto Asperger's syndrome and Rett's syndrome, autistic disorders,childhood autism and overactive disorder associated with mentalretardation and stereotyped movements, specific developmental disorderof motor function, specific developmental disorders of scholasticskills; postnatal (postpartum) and prenatal depression; eatingdisorders, including but not limited to anorexia nervosa, bulimianervosa, pica and binge eating disorder; Parkinson's disease; secondParkinsonism, such as post encephalitic Parkinsonism; Parkinsonismcomprised in other disorders; Lewis body disease; degenerative diseasesof the basal ganglia; other extrapyramidal and movement disordersincluding but not limited to tremor, essential tremor and drug-inducedtremor, myoclonus, chorea and drug-induced chorea, drug-induced tics andtics of organic origin, drug-induced acute dystonia, drug-inducedtardive dyskinesia, L-dopa-induced dyskinesia; neuroleptic-inducedmovement disorders including but not limited to neuroleptic malignantsyndrome (NMS), neuroleptic induced parkinsonism, neuroleptic-inducedearly onset or acute dyskinesia, neuroleptic-induced acute dystonia,neuroleptic-induced acute akathisia, neuroleptic-induced tardivedyskinesia, neuroleptic-induced tremor; restless leg syndrome, Stiff-mansyndrome; dystonia including but not limited to focal dystonia,multiple-focal or segmental dystonia, torsion dystonia, hemispheric,generalized and tardive dystonia (induced by psychopharmacologicaldrugs). Focal dystonia include cervical dystonia (torticolli),blepharospasm (cramp of the eyelid), appendicular dystonia (cramp in theextremities, like the writer's cramp), oromandibular dystonia andspasmodic dysphonia (cramp of the vocal cord); epilepsy, includinglocalization-related (focal)(partial) idiopathic epilepsy and epilepticsyndromes with seizures of localized onset, localization-related(focal)(partial) symptomatic epilepsy and epileptic syndromes withsimple partial seizures, localization-related (focal)(partial)symptomatic epilepsy and epileptic syndromes with complex partialseizures, generalized idiopathic epilepsy and epileptic syndromesincluding but not limited to myoclonic epilepsy in infancy, neonatalconvulsions (familial), childhood absence epilepsy (pyknolepsy),epilepsy with grand mal seizures on awakening, absence epilepsy,myoclonic epilepsy (impulsive petit mal) and nonspecific atonic, clonic,myoclonic, tonic, tonic-clonic epileptic seizures; epilepsy withmyoclonic absences, myoclonic-astatic seizures, infantile spasms,Lennox-Gastaut syndrome, Salaam attacks, symptomatic early myoclonicencephalopathy, West's syndrome, petit and grand mal seizures; statusepilepticus; persistent somatoform disorders; acute, chronic and chronicintractable pain, headache; acute and chronic pain related tophysiological processes and physical disorders including but not limitedto back pain, tooth pain, abdominal pain, low back pain, pain in joints;acute and chronic pain that is related to diseases of themusculoskeletal system and connective tissue including, but not limitedto rheumatism, myalgia, neuralgia and fibromyalgia; acute and chronicpain that is related to nerve, nerve root and plexus disorders, such astrigeminal pain, postzoster neuralgia, phantom limb syndrome with pain,carpal tunnel syndrome, lesion of sciatic nerve, diabeticmononeuropathy; acute and chronic pain that is related topolyneuropathies and other disorders of the peripheral nervous system,such as hereditary and idiopathic neuropathy, inflammatorypolyneuropathy, polyneuropathy induced by drugs, alcohol or toxicagents, polyneuropathy in neoplastic disease, diabetic polyneuropathy;and acute neurodegeneration, such as intracranial brain injuries, suchas stroke, diffuse and local brain injuries, epidural, subdural andsubarachnoid haemorrhage, and chronic neurodegeneration, such asAlzheimer's disease, Huntington's disease, multiple sclerosis, and ALS;subarachnoid haemorrhage, intracerebral haemorrhage and othernontraumatic intracranial haemorrhage, cerebral infarction, stroke,occlusion and stenosis or precerebral and cerebral arteries, notresulting in cerebral infarction, dissection of cerebral arteries,cerebral aneurysm, cerebral atherosclerosis, progressive vascularleukoencephalopathy, hypertensive encephalopathy, nonpyogenic thrombosisof intracranial venous system, cerebral arteritis, cerebral amyloidangiopathy and sequelae of cerebrovascular diseases; glaucoma and otherneuropathies; dementias, vascular dementia, Lewy body dementia,frontotemporal dementia, and HIV-dementia; vertigo and nystagmus;tinnitus; neuropsychiatric systemic lupus erythematosus; disruptive mooddysregulation disorder; schizophrenia spectrum disorder; and sleep/wakedisorders.

In treatment methods according to the invention, an effective amount ofa pharmaceutical agent according to the invention is administered to asubject suffering from or diagnosed as having such a disease, disorder,or condition. An “effective amount” means an amount or dose sufficientto generally bring about the desired therapeutic or prophylactic benefitin patients in need of such treatment for the designated disease,disorder, or condition. Effective amounts or doses of the compounds ofthe present invention may be ascertained by routine methods such asmodeling, dose escalation studies or clinical trials, and by taking intoconsideration routine factors, e.g., the mode or route of administrationor drug delivery, the pharmacokinetics of the compound, the severity andcourse of the disease, disorder, or condition, the subject's previous orongoing therapy, the subject's health status and response to drugs, andthe judgment of the treating physician. An example of a dose is in therange of from about 0.001 to about 200 mg of compound per kg ofsubject's body weight per day, preferably about 0.05 to 100 mg/kg/day,or about 1 to 35 mg/kg/day, in single or divided dosage units (e.g.,BID, TID, QID). For a 70-kg human, an illustrative range for a suitabledosage amount is from about 0.05 to about 7 g/day, or about 0.2 to about2.5 g/day.

Once improvement of the patient's disease, disorder, or condition hasoccurred, the dose may be adjusted for preventative or maintenancetreatment. For example, the dosage or the frequency of administration,or both, may be reduced as a function of the symptoms, to a level atwhich the desired therapeutic or prophylactic effect is maintained. Ofcourse, if symptoms have been alleviated to an appropriate level,treatment may cease. Patients may, however, require intermittenttreatment on a long-term basis upon any recurrence of symptoms.

In addition, the active agents of the invention may be used incombination with additional active ingredients in the treatment of theabove conditions. The additional active ingredients may beco-administered separately with an active agent of compounds of Table 1or included with such an agent in a pharmaceutical composition accordingto the invention. In an exemplary embodiment, additional activeingredients are those that are known or discovered to be effective inthe treatment of conditions, disorders, or diseases mediated by GluN2Bactivity, such as another GluN2B modulator or a compound active againstanother target associated with the particular condition, disorder, ordisease. The combination may serve to increase efficacy (e.g., byincluding in the combination a compound potentiating the potency oreffectiveness of an active agent according to the invention), decreaseone or more side effects, or decrease the required dose of the activeagent according to the invention.

The active agents of the invention are used, alone or in combinationwith one or more additional active ingredients, to formulatepharmaceutical compositions of the invention. A pharmaceuticalcomposition of the invention comprises: (a) an effective amount of atleast one active agent in accordance with the invention; and (b) apharmaceutically acceptable excipient.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluent to facilitate administration of an agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols.

Delivery forms of the pharmaceutical compositions containing one or moredosage units of the active agents may be prepared using suitablepharmaceutical excipients and compounding techniques known or thatbecome available to those skilled in the art. The compositions may beadministered in the inventive methods by a suitable route of delivery,e.g., oral, parenteral, rectal, topical, or ocular routes, or byinhalation.

The preparation may be in the form of tablets, capsules, sachets,dragees, powders, granules, lozenges, powders for reconstitution, liquidpreparations, or suppositories. Preferably, the compositions areformulated for intravenous infusion, topical administration, or oraladministration.

For oral administration, the compounds of the invention can be providedin the form of tablets or capsules, or as a solution, emulsion, orsuspension. To prepare the oral compositions, the compounds may beformulated to yield a dosage of, e.g., from about 0.05 to about 100mg/kg daily, or from about 0.05 to about 35 mg/kg daily, or from about0.1 to about 10 mg/kg daily. For example, a total daily dosage of about5 mg to 5 g daily may be accomplished by dosing once, twice, three, orfour times per day.

Oral tablets may include a compound according to the invention mixedwith pharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavoring agents, coloring agents and preservative agents.Suitable inert fillers include sodium and calcium carbonate, sodium andcalcium phosphate, lactose, starch, sugar, glucose, methyl cellulose,magnesium stearate, mannitol, sorbitol, and the like. Exemplary liquidoral excipients include ethanol, glycerol, water, and the like. Starch,polyvinyl-pyrrolidone (PVP), sodium starch glycolate, microcrystallinecellulose, and alginic acid are suitable disintegrating agents. Bindingagents may include starch and gelatin. The lubricating agent, ifpresent, may be magnesium stearate, stearic acid or talc. If desired,the tablets may be coated with a material such as glyceryl monostearateor glyceryl distearate to delay absorption in the gastrointestinal tractor may be coated with an enteric coating.

Capsules for oral administration include hard and soft gelatin capsules.To prepare hard gelatin capsules, compounds of the invention may bemixed with a solid, semi-solid, or liquid diluent. Soft gelatin capsulesmay be prepared by mixing the compound of the invention with water, anoil such as peanut oil or olive oil, liquid paraffin, a mixture of monoand di-glycerides of short chain fatty acids, polyethylene glycol 400,or propylene glycol.

Liquids for oral administration may be in the form of suspensions,solutions, emulsions or syrups or may be lyophilized or presented as adry product for reconstitution with water or other suitable vehiclebefore use. Such liquid compositions may optionally contain:pharmaceutically-acceptable excipients such as suspending agents (forexample, sorbitol, methyl cellulose, sodium alginate, gelatin,hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel andthe like); non-aqueous vehicles, e.g., oil (for example, almond oil orfractionated coconut oil), propylene glycol, ethyl alcohol, or water;preservatives (for example, methyl or propyl p-hydroxybenzoate or sorbicacid); wetting agents such as lecithin; and, if desired, flavoring orcoloring agents.

The active agents of this invention may also be administered by non-oralroutes. For example, the compositions may be formulated for rectaladministration as a suppository. For parenteral use, includingintravenous, intramuscular, intraperitoneal, or subcutaneous routes, thecompounds of the invention may be provided in sterile aqueous solutionsor suspensions, buffered to an appropriate pH and isotonicity or inparenterally acceptable oil. Suitable aqueous vehicles include Ringer'ssolution and isotonic sodium chloride. Such forms will be presented inunit-dose form such as ampules or disposable injection devices, inmulti-dose forms such as vials from which the appropriate dose may bewithdrawn, or in a solid form or pre-concentrate that can be used toprepare an injectable formulation. Illustrative infusion doses may rangefrom about 1 to 1000 μg/kg/minute of compound, admixed with apharmaceutical carrier over a period ranging from several minutes toseveral days.

For topical administration, the compounds may be mixed with apharmaceutical carrier at a concentration of about 0.1% to about 10% ofdrug to vehicle. Another mode of administering the compounds of theinvention may utilize a patch formulation to affect transdermaldelivery. Compounds of the invention may alternatively be administeredin methods of this invention by inhalation, via the nasal or oralroutes, e.g., in a spray formulation also containing a suitable carrier.

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples that follow.Artisans will recognize that, to obtain the various compounds herein,starting materials may be suitably selected so that the ultimatelydesired substituents will be carried through the reaction scheme with orwithout protection as appropriate to yield the desired product.Alternatively, it may be necessary or desirable to employ, in the placeof the ultimately desired substituent, a suitable group that may becarried through the reaction scheme and replaced as appropriate with thedesired substituent. Unless otherwise specified, the variables are asdefined above in reference to Formula (I). Reactions may be performedbetween the melting point and the reflux temperature of the solvent, andpreferably between 0° C. and the reflux temperature of the solvent.Reactions may be heated employing conventional heating or microwaveheating. Reactions may also be conducted in sealed pressure vesselsabove the normal reflux temperature of the solvent.

Abbreviations and acronyms used herein include the following:

TABLE 2 Term Acronym Aqueous aq Atmosphere atm tert-Butylcarbamoyl BocBroad br Diatomaceous Earth Celite ® Electrospray ionization ESINormal-phase silica gel chromatography FCC GluNR2B * GluN_(2B), NMDA-R2B, NR2B, hNR3 Grams g Hours h High-pressure liquid chromatography HPLCHertz Hz Isopropyl alcohol iPrOH, IPA Liquid chromatography and massspectrometry LCMS Molar M Mass to charge ratio m/z Milligrams mg Minutemin Milliliter mL Microliter μL Millimoles mmol Mass spectrometry MSNormal N Nuclear magnetic resonance NMR Parts per million ppmPrecipitate ppt Polytetrafluoroethylene PTFE Retention time R_(t) Roomtemperature rt Saturated sat Supercritical Fluid Chromatography SFCTemperature T Thin layer chromatography TLC Volume in milliliters ofsolvent per gram of substrate V, or volumes * (Collingridge, G. L, etal, Neuropharmacology, 2009, 56, 2-5)

PREPARATIVE EXAMPLES

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples to follow.

According to SCHEME 1, commercially available or syntheticallyaccessible 6-bromo-1H-pyrazolo[4,3-b]pyridine is halogenated underconditions known to one skilled in the art, to provide a compound offormula (V). For example, 6-bromo-1H-pyrazolo[4,3-b]pyridine isfluorinated using an electrophilic fluorine source such as,N-fluorobenzenesulfonimide (NFSI), N-fluoro-o-benzenedisulfonimide(NFOBS), or 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanebis(tetrafluoroborate) (Selectflor®), preferably Selectflor®; in asuitable solvent such as acetonitrile (ACN), and the like; attemperatures ranging from 0 to 100° C.; to provide a compound of formula(V), where R¹ is F.

According to SCHEME 2, a heterocyclic methanol compound of formula (VII)is obtained by reduction of commercially available or syntheticallyaccessible heterocyclic carboxylate derivative, such as an ester offormula (VI), where het is an optionally substituted five or sixmembered heteroaromatic ring containing one, two, three or fourheteroatoms independently selected from N, S, and O; and R^(b) isC₁₋₂alkyl. For example, a compound of formula (VI) is reacted with areducing agent such as sodium borohydride, lithium aluminum hydride,diisobutylaluminum hydride, and the like; in a suitable solvent such asethanol, THF, DCM, and the like; to afford a heterocyclic methanolcompound of formula (VII).

A compound of formula (VI), where het is pyridine substituted with OH,is derivatized prior to reduction to the alcohol compound of formula(VII). For example, ethyl 6-methylpyridazine-3-carboxylate is alkylatedwith sodium chlorodifluoroacetate, a base such as Cs₂CO₃, in a suitablesolvent such as DMF, at a temperature of about 100° C., to providemethyl 5-(difluoromethoxy)pyridine-3-carboxylate. A compound of formula(VI), where het is pyridine substituted with (C═O)H, is derivatizedfirst before reduction to the alcohol. For example, methyl5-formylnicotinate is reacted with diethylaminosulfur trifluoride, in asuitable solvent such as DCM, to provide methyl5-(difluoromethyl)pyridine-3-carboxylate.

A commercially available or synthetically accessible heterocyclicmethanol compound of formula (VII); where het is an optionallysubstituted five or six membered heteroaromatic ring containing one,two, three or four heteroatoms independently selected from N, S, and O;is halogenated, employing methods known to one skilled in the art, togive a compound of formula (VII) where L is Cl or Br. For example, acompound of formula (VII) is chlorinated with a chlorinating reagent,such as thionyl chloride; neat, or in a suitable solvent such asdichloromethane (DCM), and the like; at temperatures ranging from 0 to75° C.; to provide a compound of formula (VII), where L is Cl.

In a further example, a compound of formula (VII) is converted into apseudo-halide such as a mesylate, triflate, or a para-toluene sulfonateunder conditions known to one skilled in the art. For example, acompound of formula (VII) is reacted with methanesulfonyl chloride; in asuitable solvent such as dichloromethane, and the like; a tertiary aminebase such as triethylamine, and the like; at temperatures ranging from0° C. to ambient room temperature; to afford a compound of formula(VIII) where L is OsO₂CH₃.

A compound of formula (VIII), where L is Cl, and het is an optionallysubstituted five or six membered heteroaromatic ring containing one,two, three or four heteroatoms independently selected from N, S, and O;is protected employing established methodologies. For example,3-(chloromethyl)pyrazole hydrochloride is reacted with3,4-dihydro-2H-pyran, in a suitable solvent such as DMF, to provide4-(chloromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole, where theprotecting group is tetrahydro-2H-pyran-2-yl.

Difluorination of a compound of formula (XX) is achieved employingdiethylaminosulfur trifluoride (DAST), and the like, in a suitablesolvent such as DCM, to provide a compound of formula (XXI) where R^(4a)is CF₂H. A compound of formula (XX), where the Ar¹ substituted with OH,is derivatized by difluoromethylation employing sodium2-chloro-2,2-difluoroacetate, a suitable base such as NaH, in a solventsuch as DMF, and the like, to provide a compound of formula (XXII),where R^(4a) is OCF₂H. For example, 5-bromothiophene-2-carbaldehyde isdifluorinated with diethylaminosulfur trifluoride (DAST) in a suitablesolvent such as DCM, at a temperature of about 0° C. to ambient roomtemperature, to provide 2-bromo-5-(difluoromethyl)thiophene. A compoundof formula (XXI), is borylated by methods known to those skilled in theart. A compound of formula (XXI) can be treated with a transition metalcatalyst, PdCl₂dppf for example, in a solvent like DMSO or 1,4-dioxane,and a base like KOAc with bis(pinacolato)diboron to give a compound offormula (XXII). In addition, a compound of formula (XXI), is borylatedvia a metal halogen exchange of the bromide with organo-lithium ormagnesium reagents, with or without the presence of lithium chloride ata temperature of about −78° C. in a solvent like ether or THE and thelike, followed by treatment with2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane to give a compoundof formula (XXII).

According to SCHEME 4, a compound of formula (V), where R¹ is H, F, orCH₃; is alkylated with a compound of formula (VIII), where L is Cl, Br,or OsO₂CH₃; and het is an optionally substituted five or six memberedheteroaromatic ring containing one, two, three or four heteroatomsindependently selected from N, S, and O; employing a base such as NaH,K₂CO₃, Cs₂CO₃, and the like; in a suitable solvent such asdimethylformamide (DMF), tetrahydrofuran (THF), dichloromethane (DCM),and the like; to afford a compound of formula (X).

A compound of formula (X) is reacted in a metal-mediated cross couplingreaction; with a suitably substituted aryl or heteroaryl boronic acid,boronic ester, and the like; under Suzuki conditions known to oneskilled in the art; to provide a compound of Formula (I). For example, acompound of formula (X), where R¹ is H, F or CH₃; is reacted with acommercially available or synthetically accessible suitably substitutedaryl or heteroaryl boronic acid, boronic ester, and the like; in thepresence of a palladium catalyst such as(2-dicyclohexylphosphino-2′,6′-diisopropoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)methanesulfonate (RuPhos-Pd-G3),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)(PdCl₂(dppf)), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh₃)₄), andthe like; a base such as K₃PO₄, K₂CO₃, Na₂CO₃, Cs₂CO₃, and the like;potassium fluoride; in a suitable solvent such as 1,4-dioxane, DMF,ethanol, water, or a mixture thereof; at temperatures ranging from 60 to150° C.; employing conventional or microwave heating; to afford acompound of Formula (I). A compound of formula (V) is reacted in a metalmediated cross coupling reaction as previously described, with suitablysubstituted aryl or heteroaryl boronic acid, boronic ester; to provide acompound of formula (IX).

A compound of formula (IX), where R¹ is H, F, or CH₃; is alkylatedemploying conditions previously described, with a compound of formula(VIII), where L is Cl, Br, or OsO₂CH₃; and het is an optionallysubstituted five or six membered heteroaromatic ring containing one,two, three or four heteroatoms independently selected from N, S, and O;to provide a compound of Formula (I).

A compound of formula (IX) is reacted with a compound of formula (VII),where het is an optionally substituted five or six memberedheteroaromatic ring containing one, two, three or four heteroatomsindependently selected from N, S, and O; under Mitsunobu conditions, toprovide a compound of Formula (I). For example, usingtriphenylphosphine, polymer bound triphenylphosphine, and the like; abase such as di-tert-butyl azodicarboxylate (DBAD), di-tert-butylazodicarboxylate (DIAD), diethyl azodicarboxylate (DEAD) and the like;in a solvent such as THF, ACN, dioxane, or a mixture thereof; at atemperature ranging from 25 to 110° C.; to provide a compound of Formula(I).

Wherein when a (VIII) has a protecting group, deprotection employingconditions known to one skilled in the art provides a compound ofFormula (I). For example6-[3-(difluoromethoxy)-4-fluoro-phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridine,and the protecting group is tetrahydropyranyl. Deprotection is achievedemploying a suitable acid such as HCl in dioxane.

A compound of Formula (I), where R² is N

is reacted in a coupling reaction previously described with zinccyanide, [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),complex with dichloromethane, in a suitable solvent such as DMF, DMA,and the like; at temperatures ranging from rt to 150° C.; undermicrowave irradiation; provides a compound of Formula (I), where R² is

A compound of Formula (I), where R² is

undergoes classic pyridinium hydrochloride (Pyr,HCl) melt demethylation,at a temperature of about 190° C., for a period of about 24 hr, toprovide a compound of Formula (I) where R² is

According to SCHEME 5, a compound of formula (IX) where R¹ is H, F, orCH₃, and Ar¹ is as defined in claim 1; is reacted with an alkylatingagent such as ethyl bromoacetate, ethyl chloroacetate, and the like; ina suitable solvent such as DMF, and the like; a base such as Cs₂CO₃,K₂CO₃, and the like; at temperatures ranging from 0° C. to ambienttemperature; affords a compound of formula (XI), where R^(b) is CH₂CH₃.A compound of formula (XI) is hydrolyzed to the acid compound of formula(XII) using a suitable base such as NaOH, LiOH, KOH, and the like; in asuitable solvent such as MeOH, EtOH, THF, 1,4-dioxane, MeCN, H₂O, or amixture thereof.

A compound of formula (XI), where R^(b) is CH₂CH₃, is reacted underhydrazinolysis conditions, to provide a compound of formula (XIII),where R^(g) is NH₂. For example, reaction of a compound of formula (XI),where R^(b) is CH₂CH₃, and Ar¹ is as defined as in claim 1; withhydrazine hydrate; in a suitable solvent such as EtOH, and the like; attemperatures ranging from rt to 70° C., for a period of 24-72 hr;provides a compound of formula (XIII) where R^(g) is NH₂. A1,2,4-triazole compound of formula (XV), where R^(b) is CH₃, and Ar¹ isas described in claim 1; is prepared by reaction of a hydrazide compoundof formula (XIII); with an imidate compound of formula (XIV), whereR^(b) is CH₃; a base such triethylamine (TEA); in a suitable solventsuch as EtOH, and the like; at temperatures of about 70-90° C.

A hydrazide compound of formula (XIII), where R^(g) is NH₂, is preparedin two steps from a compound of formula (XI), where R^(b) is H. In afirst step, a compound of formula (XI), where R^(b) is H; is convertedto the corresponding acid chloride using a reagent such as thionylchloride, oxalyl chloride, and the like; in a suitable solvent such asTHF, DMF, or ACN. In a second step, hydrazinolysis of the acid chlorideintermediate is achieved employing conditions previously described toprovide a hydrazide compound of formula (XIII). A compound of formula(XVI), where R^(c) is H, and Ar¹ is as described in claim 1; is preparedin two steps form hydrazide compound of formula (XIII). In a first step,a compound of formula (XIII), where R^(g) is NH₂, is reacted withtriethyl orthoformate; at a temperature of about 140° C.; for a periodof about 24 hours; to provide the formyl intermediate compound which wasused in the next step directly. Cyclodehydration of the formylintermediate compound employing an acid such asp-toluenesulfonic acidmonohydrate (TsOH), acetic acid (AcOH), and the like, preferably TsOH;provides the corresponding 1,3,4-oxadiazole compound of formula (XVI),where R^(c) is H.

A compound of formula (XI) converted to a compound of formula (XVIII)employing conventional amide bond forming techniques such as couplingreactions which are well known to those skilled in the art. For example,reaction of compound of formula (XVII), where R^(b) is H or CH₃; with anacid compound of formula (XI), where R^(b) is H; where the acid isactivated with an appropriate activating reagent, for example acarbodiimide, such as N,N′-dicyclohexylcarbodiimide (DCC) or1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDAC or EDCI)optionally in the presence of hydroxybenzotriazole (HOBt) and/or acatalyst such as 4-dimethylaminopyridine (DMAP); ahalotrisaminophosphonium salt such as(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate(BOP), or bromotripyrrolidinophosphonium hexafluorophosphate (PyBroP®);a suitable pyridinium salt such as 2-chloro-1-methyl pyridiniumchloride; or another suitable coupling agent such asN,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uroniumhexafluorophosphate (HBTU),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate (HATU),2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (T3P®)and the like, provides a compound of formula (XVIII). Coupling reactionsare conducted in a suitable solvent such as DCM, THF, DMF and the like,optionally in the presence of a tertiary amine such asN-methylmorpholine, N-ethyldiisopropylamine (DIEA, DIPEA), ortriethylamine (TEA), at a temperature ranging from about 0° C. to rt, toprovide compound a of formula (XVIII). Thionation followed byspontaneous ring closure through dehydrosulfurization of a compound offormula (XVIII), where R^(b) is H or CH₃, with2,4-bis(4-methoxyphenyl)-1,2,3,4-dithiadiphosphetane (Lawesson'sreagent), in suitable solvent such as toluene, and the like; attemperatures of about 105° C.; for a period of about 24 hr; affords athiadiazole compound of formula (XIX), where R^(c) is NH₂ or NHCH₃. Athiadiazole compound of formula (XIX), where R^(c) is NH₂ is acylatedemploying an acylating reagent selected from an acyl derivative, an acylhalide such as acetyl chloride and the like, and an acid anhydride suchas acetic anhydride, propionic anhydride, and the like; in a suitablesolvent such as toluene, and the like; to afford a thiadiazole compoundof formula (XIX), where R^(c) is NH(C═O)CH₃.

Compounds of Formula (I) may be converted to their corresponding saltsusing methods known to one of ordinary skill in the art. For example, anamine of Formula (I) is treated with trifluoroacetic acid, HCl, orcitric acid in a solvent such as Et₂O, CH₂Cl₂, THF, MeOH, chloroform, orisopropanol to provide the corresponding salt form. Alternately,trifluoroacetic acid or formic acid salts are obtained as a result ofreverse phase HPLC purification conditions. Crystalline forms ofpharmaceutically acceptable salts of compounds of Formula (I) may beobtained in crystalline form by recrystallization from polar solvents(including mixtures of polar solvents and aqueous mixtures of polarsolvents) or from non-polar solvents (including mixtures of non-polarsolvents).

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.

Compounds prepared according to the schemes described above may beobtained as single forms, such as single enantiomers, by form-specificsynthesis, or by resolution. Compounds prepared according to the schemesabove may alternately be obtained as mixtures of various forms, such asracemic (1:1) or non-racemic (not 1:1) mixtures. Where racemic andnon-racemic mixtures of enantiomers are obtained, single enantiomers maybe isolated using conventional separation methods known to one ofordinary skill in the art, such as chiral chromatography,recrystallization, diastereomeric salt formation, derivatization intodiastereomeric adducts, biotransformation, or enzymatic transformation.Where regioisomeric or diastereomeric mixtures are obtained, asapplicable, single isomers may be separated using conventional methodssuch as chromatography or crystallization.

The following specific examples are provided to further illustrate theinvention and various preferred embodiments.

EXAMPLES

In obtaining the compounds described in the examples below and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt) under a nitrogen atmosphere. Where solutions were“dried,” they were generally dried over a drying agent such as Na₂SO₄ orMgSO₄. Where mixtures, solutions, and extracts were “concentrated”, theywere typically concentrated on a rotary evaporator under reducedpressure. Reactions under microwave irradiation conditions were carriedout in a Biotage Initiator or CEM (Microwave Reactor) Discoverinstrument.

For the reactions conducted under continuous flow conditions, “flowedthrough a LTF-VS mixer” refers to the use of a Chemyx Fusion 100 TouchSyringe Pump that is in line via 1/16″ PTFE tubing to a LTF-VS mixer(Little Things Factory GmbH (http://www.ltf-gmbh.com), unless otherwiseindicated.

Normal-phase silica gel chromatography (FCC) was performed on silica gel(SiO₂) using prepacked cartridges.

Preparative reverse-phase high performance liquid chromatography (RPHPLC) was performed on either:

METHOD A. An Agilent HPLC with an Xterra Prep RP18 column (5 μM, 30×100or 50×150 mm) or an XBridge C18 OBD column (5 μM, 30×100 or 50×150 mm),and a mobile phase of 5% ACN in 20 mM NH₄OH was held for 2 min, then agradient of 5-99% ACN over 15 min, then held at 99% ACN for 5 min, witha flow rate of 40 or 80 mL/min.

or

METHOD B. A Shimadzu LC-8A Series HPLC with an Inertsil ODS-3 column (3μm, 30×100 mm, T=45° C.), mobile phase of 5% ACN in H₂O (both with 0.05%TFA) was held for 1 min, then a gradient of 5-99% ACN over 6 min, thenheld at 99% ACN for 3 min, with a flow rate of 80 mL/min.

or

METHOD C. A Shimadzu LC-8A Series HPLC with an XBridge C18 OBD column (5μm, 50×100 mm), mobile phase of 5% ACN in H₂O (both with 0.05% TFA) washeld for 1 min, then a gradient of 5-99% ACN over 14 min, then held at99% ACN for 10 min, with a flow rate of 80 mL/min.

or

METHOD D. A Gilson HPLC with an XBridge C18 column (5 μm, 100×50 mm),mobile phase of 5-99% ACN in 20 mM NH₄OH over 10 min and then hold at 99ACN for 2 min, at a flow rate of 80 mL/min.

or

METHOD E. A Wufeng LC100 equipped with a manual Rheodyne 3725i samplerwith a Gemini-NX C18 column (5 μM, 30×100 mm), and a mobile phase of0-90% MeCN:8 mM (NH₄)HCO₃ (9:1) in 10 mM aqueous (NH₄)HCO₃ over 8 min or21 min, with a flow rate of 40 mL/min.

or

METHOD F. An AccuPrep HPLC with an XBridge C18 column (5 μm, 100×50 mm),mobile phase of 5-99% ACN in 20 mM NH₄OH over 18 min and then hold at 99ACN for 2 min, at a flow rate of 80 mL/min.

or

METHOD G: An AccuPrep HPLC with an XBridge C18 column (5 μm, 100×50 mm),mobile phase of 5% ACN in H₂O (both with 0.05% TFA) was held for 1 min,then a gradient of 5-99% ACN over 18 min, then held at 99% ACN for 2min, with a flow rate of 80 mL/min.

Preparative supercritical fluid high performance liquid chromatography(SFC) was performed either on a Jasco preparative SFC system, an APS1010 system from Berger instruments, or a SFC-PICLAB-PREP 200 (PICSOLUTION, Avignon, France). The separations were conducted at 100 to 150bar with a flow rate ranging from 40 to 60 mL/min. The column was heatedto 35 to 40° C.

Mass spectra (MS) were obtained on an Agilent series 1100 MSD usingelectrospray ionization (ESI) in positive mode unless otherwiseindicated. Calculated (calcd.) mass corresponds to the exact mass.

Nuclear magnetic resonance (NMR) spectra were obtained on Bruker modelDRX spectrometers. Definitions for multiplicity are as follows:s=singlet, d=doublet, t=triplet, q=quartet, m=multiplet, br=broad. Itwill be understood that for compounds comprising an exchangeable proton,said proton may or may not be visible on an NMR spectrum depending onthe choice of solvent used for running the NMR spectrum and theconcentration of the compound in the solution.

Chemical names were generated using ChemDraw Ultra 17.1 (CambridgeSoftCorp., Cambridge, Mass.) or OEMetaChem V1.4.0.4 (Open Eye).

Compounds designated as R* or S* are enantiopure compounds where theabsolute configuration was not determined.

Intermediate 1: (Racemic)4-(Chloromethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole

To a solution of 3-(chloromethyl)pyrazole hydrochloride (875 mg, 5.72mmol) in N,N-dimethylformamide (DMF) (17 mL) was added3,4-dihydro-2H-pyran (1.8 mL, 19.7 mmol, 0.922 g/mL). The reactionmixture was stirred at room temperature for 18 h, poured into water (100mL) and extracted with diethyl ether (Et₂O) (3×50 mL). The combinedorganics were washed with brine (2×30 mL), dried over magnesium sulfate(MgSO₄), filtered and concentrated. Purification (FCC, SiO₂, 0 to 25%n-heptane/EtOAc) afforded the title compound (760 mg, 3.79 mmol, 66%) asa pale yellow oil. MS (ESI): mass calcd. for C₉H₁₃ClN₂O; 200.1 m/zfound, 201.1 [M+H]⁺.

Intermediate 2: 3-(Chloromethyl)-6-methylpyridazine hydrochloride Salt

Step A. (6-Methylpyridazin-3-yl)methanol. To a solution of ethyl6-methylpyridazine-3-carboxylate (200 mg, 1.2 mmol) in methanol (MeOH)(3 mL) and tetrahydrofuran (THF) (1.5 mL) was added sodium borohydride(46 mg, 1.22 mmol) at 0° C. The reaction mixture was stirred for 10 minat 0° C. then allowed to warm to room temperature and stirred for 1.5 h.1 M HCl was added (pH˜8) and the mixture concentrated. Purification ofthe residue (FCC, SiO₂, 0 to 10% MeOH in DCM) afforded the titlecompound (97 mg, 0.781 mmol, 65%) as a yellow crystalline solid. MS(ESI): mass calcd. for C₆H₈N₂O; 124.1 m/z found, 125.1 [M+H]⁺.

Step B. 3-(Chloromethyl)-6-methyl-pyridazine hydrochloride. To(6-methylpyridazin-3-yl)methanol (89 mg, 0.717 mmol) was added thionylchloride (273 μL, 3.76 mmol, 1.64 g/mL) at 0° C. and the reaction wasstirred at room temperature for 2 h. The mixture was concentrated andthe residue was taken up in toluene (3 mL) then concentrated again togive the title compound (127 mg, 0.709 mmol, 98%) as a brown powder. MS(ESI): mass calcd. for C₆H₇ClN₂; 142.0 m/z found, 143.1 [M+H]⁺.

Intermediate 3: 3-(Chloromethyl)-5-(difluoromethoxy)pyridinehydrochloride Salt

Step A. Methyl 5-(difluoromethoxy)pyridine-3-carboxylate. A mixture ofmethyl 5-hydroxynicotinate (1.00 g, 6.53 mmol), sodiumchlorodifluoroacetate (2.2 g, 14.4 mmol) and cesium carbonate (Cs₂CO₃)(6.40 g, 19.6 mmol) in dry DMF (20 mL) was stirred at 100° C. for 3 h.The reaction mixture was poured into water (80 mL) and diluted withEtOAc (100 mL). The layers were separated, and the aqueous layer wasextracted with EtOAc (2×80 mL). The combined organic layers were driedover MgSO₄, filtered and concentrated. Purification (FCC, SiO₂, 0 to 30%n-heptane/EtOAc) afforded the title compound (357 mg, 1.76 mmol, 27%) asa pale yellow oil. MS (ESI): mass calcd. for C₈H₇F₂NO₃; 203.0 m/z found,204.1 [M+H]⁺.

Step B. [5-(Difluoromethoxy)-3-pyridyl]methanol. To a solution of methyl5-(difluoromethoxy)pyridine-3-carboxylate (265 mg, 1.30 mmol) in MeOH(5.3 mL) and THE (2.7 mL) was added sodium borohydride (99 mg, 2.62mmol) at 0° C. and the reaction mixture was stirred at room temperaturefor 20 h. To the reaction mixture was added additional sodiumborohydride (99 mg, 2.62 mmol) and the reaction mixture was stirred atroom temperature for 2 h. More sodium borohydride (50 mg, 1.32 mmol) wasadded and the reaction mixture was stirred at room temperature for 2 h.1 M HCl was added (pH-8) and the mixture concentrated. The residue wastaken up in MeOH (15 mL) then filtered and concentrated. Purification(FCC, SiO₂, 0 to 5% DCM/MeOH) afforded the title compound (128 mg, 0.731mmol, 56%) as a pale yellow oil. MS (ESI): mass calcd. for C₇H₆F₂NO₂;174.0 m/z found, 175.1 [M+H]⁺.

Step C. 3-(Chloromethyl)-5-(difluoromethoxy)pyridine hydrochloride. To[5-(difluoromethoxy)-3-pyridyl]methanol (118 mg, 0.674 mmol) was addedthionyl chloride (257 μL, 3.54 mmol, 1.64 g/mL) at 0° C. and thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was concentrated, and the residue was taken up in toluene (3 mL)and concentrated again to give the title compound (133 mg, 0.578 mmol,86%) as an off-white powder. MS (ESI): mass calcd. for C₇H₆ClF₂NO₂;193.0 m/z found, 194.0 [M+H]⁺.

Intermediate 4: 3-(Chloromethyl)-5-(difluoromethyl)pyridinehydrochloride Salt

Step A. Methyl 5-(difluoromethyl)pyridine-3-carboxylate. To a solutionof methyl 5-formylnicotinate (500 mg, 3.03 mmol) in DCM (10 mL) wasadded diethylaminosulfur trifluoride (520 μL, 3.94 mmol, 1.22 g/mL) at0° C. The reaction mixture was allowed to reach room temperature andstirred for 18 h under argon. The reaction mixture was cooled to 0° C.and quenched with saturated aqueous NaHCO₃ (10 mL). The layers wereseparated and the aqueous layer extracted with DCM (2×10 mL). Thecombined organic layers were dried over MgSO₄, filtered and concentratedto afford the title compound (467 mg, 2.49 mmol, 82%) as a yellowcrystalline solid. MS (ESI): mass calcd. for C₈H₇F₂NO₂; 187.0 m/z found,188.1 [M+H]⁺. Step B. (5-(Difluoromethyl)pyridin-3-yl)methanol. To asolution of methyl 5-(difluoromethyl)pyridine-3-carboxylate (160 mg,0.855 mmol) in DCM (3.2 mL) cooled to 0° C. was added diisobutylaluminumhydride (1.0 M in DCM, 1.8 mL, 1.80 mmol). The reaction was stirred at0° C. for 1 h under argon then additional diisobutylaluminum hydride(1.0 M in DCM, 769 μL, 0.769 mmol) was added. The reaction mixture wasstirred at 0° C. for another 1 h then quenched with MeOH (5 mL),filtered, and concentrated. Purification (FCC, SiO₂, 0 to 5% DCM/MeOH)afforded the title compound (40 mg) as a yellow oil. MS (ESI): masscalcd. for C₇H₇F₂NO; 159.0 m/z found, 160.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.70-8.67 (m, 1H), 8.67-8.63 (m, 1H), 7.96-7.90 (m, 1H), 7.16(t, J=55.3 Hz, 1H), 5.45 (t, J=5.7 Hz, 1H), 4.61 (d, J=5.7 Hz, 2H).

Step C. 3-(Chloromethyl)-5-(difluoromethyl)pyridine hydrochloride. To[5-(difluoromethyl)-3-pyridyl]methanol (37 mg) was added thionylchloride (89 μL, 1.23 mmol, 1.64 g/mL) at 0° C. The reaction mixture wasstirred at room temperature for 2 h then concentrated. The residue wastaken up in DCM (2 mL) and concentrated to afford the title compound (44mg, 0.206 mmol, 88%) as an off-white powder. MS (ESI): mass calcd. forC₇H₆ClF₂N; 177.0 m/z found, 178.0 [M+H]⁺.

Intermediate 5: 2-(Chloromethyl)-5-methylthiophene

To a solution of (5-methylthiophen-2-yl)methanol (100 mg, 0.78 mmol) inDCM (1.4 mL) was added thionyl chloride (170 μL, 2.34 mmol, 1.64 g/mL)at 0° C. and the reaction mixture was stirred at room temperature for 2h. The reaction mixture was then concentrated to afford the titlecompound (108 mg, 0.737 mmol, 94%) as a dark brown oil. Crude titlecompound was used without further purification. No mass found in MS.

Intermediate 6: 2-(Chloromethyl)-5-fluorothiophene

The title compound was made in an analogous manner to Intermediate 5using (5-fluorothiophen-2-yl)methanol. Crude title compound was usedwithout further purification. No mass found in MS.

Intermediate 7: (5-Fluoropyridin-3-yl)methyl methanesulfonate

Methanesulfonyl chloride (0.04 mL, 0.5 mmol) was added to a solution of(5-fluoropyridin-3-yl)methanol (50.0 mg, 0.4 mmol) and triethylamine(TEA) (0.8 mL, 0.6 mmol) in DCM (1.7 mL) at 0° C. under a nitrogenatmosphere. After 45 minutes, the reaction mixture was quenched withwater (10 mL) and saturated aqueous NaHCO₃ (10 mL). The layers wereseparated and the aqueous layer was extracted with DCM (2×35 mL). Thecombined organics were dried over MgSO₄, filtered and concentrated toafford title compound. Crude title compound was used without furtherpurification.

Intermediate 8: Pyridazin-4-ylmethyl methanesulfonate

The title compound was prepared in a manner analogous to Intermediate 7using pyridazin-4-ylmethanol. Crude title compound was used withoutfurther purification.

Intermediate 9: (6-(Trifluoromethyl)pyridin-3-yl)methyl methanesulfonate

The title compound was prepared in a manner analogous to Intermediate 7using (6-(trifluoromethyl)pyridin-3-yl)methanol. Crude title compoundwas used without further purification.

Intermediate 10: (5-(Trifluoromethyl)pyridin-3-yl)methylmethanesulfonate

The title compound was prepared in a manner analogous to Intermediate 7using (5-(trifluoromethyl)pyridin-3-yl)methanol. Crude title compoundwas used without further purification.

Intermediate 11: (4-(Trifluoromethyl)pyridin-3-yl)methylmethanesulfonate

The title compound was prepared in a manner analogous to Intermediate 7using (4-(trifluoromethyl)pyridin-3-yl)methanol. Crude title compoundwas used without further purification.

Intermediate 12:2-(5-(Difluoromethyl)thiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step A. 2-Bromo-5-(difluoromethyl)thiophene. To dimethylaminosulfurtrifluoride (5.6 mL, 42.4 mmol, 1.22 g/mL) was added5-bromothiophene-2-carbaldehyde (2.00 g, 10.5 mmol) dropwise at 0° C.under argon. The reaction mixture was then stirred at room temperaturefor 2 h. The reaction was quenched by dropwise addition of 2 M sodiumhydroxide (NaOH) (10 mL) at 0° C. The layers were separated and theaqueous layer was extracted with EtOAc (2×20 mL). The combined organicswere dried over Na₂SO₄, filtered and concentrated. Purification (FCC,SiO₂, n-heptane) afforded title compound (1.07 g, 5.03 mmol, 48%) as acolorless liquid. No mass ion found in MS.

Step B.2-(5-(difluoromethyl)thiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.To a solution of 2-bromo-5-(difluoromethyl)thiophene (930 mg, 4.37 mmol)in THE (17 mL) was added n-butyllithium (1.6 M in hexanes, 3 mL, 4.8mmol) dropwise at −78° C. under argon and the reaction mixture wasstirred at −78° C. for 1 h. To the reaction mixture was added a solutionof 2-isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (980 μL, 4.8mmol, 0.912 g/mL) in THE (2 mL) and the reaction was stirred at −78° C.for 1 h. The reaction mixture was allowed to reach room temperature andthen stirred for 16 h. The reaction was diluted with saturated aq. NH₄Cl(30 mL) and ethyl acetate (EtOAc) (40 mL). The layers were separated andthe aqueous layer was extracted with EtOAc (1×50 mL). The combinedorganics were dried over Na₂SO₄, filtered and concentrated to give thetitle compound (1.00 g) as a brown oil that was used without furtherpurification.

Intermediate 13: 6-Bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine

To a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (2.5 g, 12.6 mmol)in acetonitrile (62.5 mL) was added1-chloromethyl-4-fluoro-1,4-diazobicyclo[2.2.2]octanebis(tetrafluoroborate) (Selectflor®) (6.7 g, 18.9 mmol) and the reactionmixture was stirred at 90° C. for 22 h. The reaction mixture was cooled,poured into water (120 mL), and was diluted with EtOAc (80 mL). Thelayers were separated and the aqueous layer was extracted with EtOAc(2×60 mL). The combined organic layers were dried over MgSO₄, filteredand concentrated. The residue was purified by basic reverse phasepreparative HPLC (METHOD E) to afford the title compound (641 mg, 2.97mmol, 23%) as a brown powder. MS (ESI): mass calcd. for C₆H₃BrFN₃; 214.9m/z found, 216.0 [M+H]⁺.

Intermediate 14:6-Bromo-1-((5-methoxypyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine

A mixture of 6-bromo-1H-pyrazolo[4,3-b]pyridine (538 mg, 2.72 mmol),3-(chloromethyl)-5-methoxypyridine hydrochloride (580 mg, 2.99 mmol) andCs₂CO₃ (2.21 g, 6.78 mmol) in dry DMF (15 mL) was stirred at roomtemperature for 4 h. The reaction mixture was poured into water (30 mL)and diluted with EtOAc (15 mL). The layers were separated and theaqueous layer was extracted with EtOAc (2×30 mL). The combined organiclayers were dried over Na₂SO₄, filtered and concentrated. Purification(FCC, SiO₂, 50 to 80% n-heptane/EtOAc) afforded the title compound (508mg, 1.59 mmol, 59%) as a pale yellow powder. MS (ESI): mass calcd forC₁₃H₁₁BrN₄O, 318.0; m/z found, 319.0 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ8.77 (s, 1H), 8.64-8.58 (m, 1H), 8.39 (s, 1H), 8.25-8.20 (m, 1H), 8.14(s, 1H), 7.33-7.26 (m, 1H), 5.70 (s, 2H), 3.79 (s, 3H).

The reaction also produced6-bromo-2-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine (232 mg,0.727 mmol, 27%) as a pale yellow powder. MS (ESI): mass calcd forC₁₃H₁₁BrN₄O, 318.0; m/z found, 319.0 [M+H]⁺.

Intermediate 15:6-Bromo-3-fluoro-1-((5-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 14using 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine (Intermediate 13)instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine and using3-(chloromethyl)-5-fluoropyridine instead of3-(chloromethyl)-5-methoxypyridine. MS (ESI): mass calcd forC₁₂H₇BrF₂N₄, 323.9; m/z found, 325.1 [M+H]⁺.

Intermediate 16:6-Bromo-3-fluoro-1-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 14using 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine (Intermediate 13)instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine and using3-(chloromethyl)pyridine instead of 3-(chloromethyl)-5-methoxypyridine.MS (ESI): mass calcd for C₁₂H₇BrF₂N₄, 305.9; m/z found, 307.1 [M+H]⁺.

Intermediate 17:6-Bromo-1-((5-(difluoromethoxy)pyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 14using 3-(chloromethyl)-5-(difluoromethoxy)pyridine instead of3-(chloromethyl)-5-methoxypyridine. MS (ESI): mass calcd forC₁₃H₉BrF₂N₄O, 353.9; m/z found, 355.0 [M+H]⁺.

Intermediate 18:6-Bromo-1-((5-chloropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 14using 3-chloro-5-(chloromethyl)pyridine instead of3-(chloromethyl)-5-methoxypyridine. MS (ESI): mass calcd forC₁₂H₈BrClN₄, 321.9; m/z found, 323.0 [M+H]⁺.

Intermediate 19:2-((6-Bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole

The title compound was made in an analogous manner to Intermediate 14using 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole instead of3-(chloromethyl)-5-methoxypyridine. MS (ESI): mass calcd for C₁₀H₈BrN₅O,292.9; m/z found, 294.0 [M+H]⁺.

Intermediate 20:2-((6-Bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole

The title compound was made in an analogous manner to Intermediate 14using 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine (Intermediate 13)instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine and using2-(chloromethyl)-5-methyl-1,3,4-oxadiazole instead of3-(chloromethyl)-5-methoxypyridine. MS (ESI): mass calcd forC₁₀H₇BrFN₅O, 310.9; m/z found, 312.0 [M+H]⁺.

Intermediate 21:5-((6-Bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)nicotinonitrile

The title compound was made in an analogous manner to Intermediate 14using 5-(chloromethyl)nicotinonitrile instead of3-(chloromethyl)-5-methoxypyridine. MS (ESI): mass calcd for C₁₃H₈BrN₅,313.0; m/z found, 314.0 [M+H]⁺.

Intermediate 22:2-((6-Bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyloxazole

The title compound was made in an analogous manner to Intermediate 14using 2-(chloromethyl)-5-methyloxazole instead of3-(chloromethyl)-5-methoxypyridine. MS (ESI): mass calcd. forC₁₁H₉BrN₄O, 292.0; m/z found, 293.0 [M+H]⁺.

Intermediate 23:5-((6-Bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-2-methyloxazole

The title compound was prepared in a manner analogous to Intermediate 14using 5-(chloromethyl)-2-methyloxazole instead of3-(chloromethyl)-5-methoxypyridine. MS (ESI): mass calcd. forC₁₁H₉BrN₄O, 292.0; m/z found, 293.0 [M+H]⁺.

Intermediate 24:2-((6-Bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-thiadiazole

The title compound was prepared in a manner analogous to Intermediate 14using 2-(chloromethyl)-5-methyl-1,3,4-thiadiazole instead of3-(chloromethyl)-5-methoxypyridine. MS (ESI): mass calcd. forC₁₀H₈BrN₅S, 309.0; m/z found, 309.9 [M+H]⁺.

Intermediate 25:6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine

A mixture of 6-bromo-1H-pyrazolo[4,3-b]pyridine (1.40 g, 7.07 mmol),2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(2.31 g, 8.49 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (0.673 g,0.92 mmol) and Na₂CO₃ (2.25 g, 21.2 mmol) in degassed acetonitrile (ACN)(24.4 mL) and water (3.76 mL) was stirred at 120° C. for 4 h undermicrowave irradiation. The reaction mixture was poured into water (30mL) and the mixture was extracted with EtOAc (3×30 mL). The combinedorganic layers were dried over Na₂SO₄, filtered and concentrated.Purification (FCC, SiO₂, 10 to 50% n-heptane/EtOAc) afforded a solidthat was triturated with Et₂O (4 mL) to afford the title compound (1.41g, 5.36 mmol, 76%) as an off-white powder. MS (ESI): mass calcd forC₁₃H₈F₃N₃, 263.1; m/z found, 264.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ13.48 (br s, 1H), 8.84 (d, J=2.0 Hz, 1H), 8.41-8.30 (m, 1H), 8.30-8.20(m, 1H), 8.13-7.99 (m, 2H), 7.60-7.49 (m, 1H), 7.27 (t, J=54.1 Hz, 1H).

Intermediate 26:6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using2-(3-(difluoromethoxy)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd for C₁₃H₈F₃N₃O, 279.0; m/z found, 280.2 [M+H]⁺.

Intermediate 27:6-(4-Chloro-3-(difluoromethoxy)phenyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using2-(3-(difluoromethoxy)-4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd for C₁₃H₈ClF₂N₃O, 295.0; m/z found, 296.0 [M+H]⁺.

Intermediate 28:6-(3-(1,1-Difluoroethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using2-(3-(1,1-difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd for C₁₄H₁₀F₃N₃, 277.1; m/z found, 278.1 [M+H]⁺.

Intermediate 29:6-(3-(1,1-Difluoroethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using2-(3-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd for C₁₄H₁₁F₂N₃, 259.1; m/z found, 260.1 [M+H]⁺.

Intermediate 30:6-(3-(Difluoromethyl)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine (Intermediate 13)instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine. MS (ESI): mass calcd forC₁₃H₇F₄N₃, 281.1; m/z found, 280.2 [M−H]⁻.

Intermediate 31:6-(4-Chloro-3-(difluoromethoxy)phenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine (Intermediate 13)instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine and2-(3-(difluoromethoxy)-4-chlorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd for C₁₃H₇ClF₃N₃O, 313.0; m/z found, 314.1 [M+H]⁺.

Intermediate 32:6-(3-(Difluoromethoxy)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine (Intermediate 13)instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine and using2-(3-(difluoromethoxy)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd for C₁₃H₇F₄N₃O, 297.1; m/z found, 298.0 [M+H]⁺.

Intermediate 33:6-(3-(1,1-Difluoroethyl)phenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using 6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridine (Intermediate 13)instead of 6-bromo-1H-pyrazolo[4,3-b]pyridine and using2-(3-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneinstead of2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd for C₁₄H₁₀F₃N₃, 277.1; m/z found, 278.1 [M+H]⁺.

Intermediate 34: 6-(4-Fluoro-3-methylphenyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using (4-fluoro-3-methylphenyl)boronic acid instead of2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd for C₁₃H₁₀FN₃, 227.1; m/z found, 228.1 [M+H]⁺.

Intermediate 35:6-(3-(Difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using 6-bromo-3-methyl-1H-pyrazolo[4,3-b]pyridine instead of6-bromo-1H-pyrazolo[4,3-b]pyridine. MS (ESI): mass calcd. forC₁₄H₁₀F₃N₃, 277.1; m/z found, 278.1 [M+H]⁺.

Intermediate 36:6-(2,4-Difluoro-3-methylphenyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using (2,4-difluoro-3-methylphenyl)boronic acid instead of2-[3-(difluoromethyl)-4-fluoro-phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₃H₉F₂N₃, 245.1; m/z found, 246.1 [M+H]⁺.

Intermediate 37:2-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)aceticAcid

Step A. Ethyl2-(6-(3-(difluoromethyl)-4-fluoro-phenyl)pyrazolo(4,3-b)pyridin-1-yl)acetate.To a solution of6-(3-(difluoromethyl)-4-fluoro-phenyl)-1H-pyrazolo(4,3-b)pyridine(Intermediate 25, 2.00 g, 7.6 mmol) in DMF (30 mL) was added Cs₂CO₃(2.72 g, 8.35 mmol) at 0° C. and the reaction was stirred at 0° C. for30 min. To the reaction mixture was added ethyl chloroacetate (895 μL,8.36 mmol, 1.14 g/mL) at 0° C. The reaction mixture was allowed to warmto room temperature and stirred for 1 h. The reaction mixture was pouredinto water (50 mL) and the mixture was extracted with EtOAc (3×75 mL).The organic layers were combined and concentrated. Purification (FCC,SiO₂, 0 to 75% n-heptane/EtOAc) afforded the title compound (1.60 g,4.580 mmol, 60%) as a white powder. MS (ESI): mass calcd forC₁₇H₁₄F₃N₃O₂, 349.1; m/z found, 350.1 [M+H]⁺.

Step B.2-(6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)aceticacid. To a solution of ethyl2-(6-(3-(difluoromethyl)-4-fluoro-phenyl)pyrazolo(4,3-b)pyridin-1-yl)acetate(1.60 g, 4.58 mmol) in 1,4-dioxane (14 mL) and water (9 mL) was addedlithium hydroxide monohydrate (385 mg, 9.17 mmol) and the mixture wasstirred at room temperature for 1 h, concentrated to ˜9 mL and dilutedwith water (75 mL). The mixture was acidified to pH 4 with 1 M HCl. Theprecipitate was collected and washed with water (2×10 mL) and Et₂O (3×10mL) to afford the title compound (1.74 g) as a white powder that wasused without further purification. MS (ESI): mass calcd forC₁₅H₁₀F₃N₃O₂, 321.1; m/z found, 322.1 [M+H]⁺.

Intermediate 38:N′-Acetyl-2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetohydrazide

A mixture of2-(6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)aceticacid (Intermediate 37, 71.7 mg, 0.223 mmol), acethydrazide (39.2 mg,0.529 mmol), N,N-diisopropylethylamine (Hunig's base) (0.12 mL, 0.696mmol), N-ethyl-N′-(3-dimethylaminopropyl)carbodiimide (EDCI) (68.2 mg,0.356 mmol), and hydroxybenzotriazole (HOBt) (48.5 mg, 0.359 mmol) wasdissolved in DMF (1.5 mL) and stirred at rt overnight. The mixture wasthen diluted with EtOAc and water, then the layers were separated, andthe aqueous layer was extracted with EtOAc (×3). The combined organiclayers were washed with water (×2) and brine (×1), then dried (Na₂SO₄)and concentrated under reduced pressure. Purification (FCC, SiO₂, 0-10%MeOH in DCM) afforded the title compound as a tan colored solid (58.6mg, 70%). MS (ESI): mass calcd. for C₁₇H₁₄F₃N₅O₂, 377.1; m/z found,378.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.82 (d, J=1.8 Hz, 1H), 8.42(dd, J=1.8, 1.0 Hz, 1H), 8.27 (d, J=1.0 Hz, 1H), 8.01 (dd, J=16.5, 7.4Hz, 2H), 7.41 (dd, J=9.9, 8.7 Hz, 1H), 7.08 (t, J=54.6 Hz, 1H), 5.35 (s,2H), 1.99 (s, 3H).

Intermediate 39:2-(6-(3-(Difluoromethyl)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-ylaceticAcid

The title compound was made in an analogous manner to Intermediate 37using Intermediate 30:6-(3-(difluoromethyl)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridineinstead of6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine. MS(ESI): mass calcd for C₁₅H₉F₄N₃O₂, 339.1; m/z found, 340.1 [M+H]⁺.

Intermediate 40:2-(6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)aceticAcid

The title compound was made in an analogous manner to Intermediate 37using 6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) instead of6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine. MS(ESI): mass calcd for C₁₅H₁₀F₃N₃O₃, 337.1; m/z found, 338.1 [M+H]⁺.

Intermediate 41: 6-(5-Chloro-2-thienyl)-1H-pyrazolo[4,3-b]pyridine

To a solution of 6-bromo-1H-pyrazolo[4,3-b]pyridine (500 mg, 2.52 mmol)in a mixture of degassed 1,4-dioxane (39.4 mL) and water (9.55 mL) wasadded 5-chlorothiophene-2-boronic acid (431 mg, 2.654 mmol), potassiumfluoride (440 mg, 7.57 mmol) andtetrakis(triphenylphosphine)palladium(0) (205 mg, 0.177 mmol) and thereaction mixture was stirred at 80° C. for 1 h under argon. Additional5-chlorothiophene-2-boronic acid (123 mg, 0.757 mmol) andtetrakis(triphenylphosphine)palladium(0) (87 mg, 0.075 mmol) wereintroduced and the reaction mixture was stirred at 80° C. for anadditional 2 h. The reaction mixture was diluted with water (40 mL) andDCM (30 mL). The layers were separated and the aqueous layer wasextracted with DCM (3×40 mL). The combined organics were dried overNa₂SO₄, filtered and concentrated. Purification (FCC, SiO₂, 25 to 100%n-heptane/EtOAc) afforded the title compound (419 mg, 1.78 mmol, 70%) asa yellow powder after triturating with diethyl ether (7 mL). MS (ESI):mass calcd. for C₁₀H₆ClN₃S, 235.0; m/z found, 236.0 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 13.42 (s, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.35-8.29 (m,1H), 8.17-8.09 (m, 1H), 7.64 (d, J=4.0 Hz, 1H), 7.25 (d, J=4.0 Hz, 1H).

Intermediate 42:6-(3-(Trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine

A suspension of 6-bromo-1H-pyrazolo[4,3-b]pyridine (5.0 g, 25.3 mmol),3-(trifluoromethyl)phenylboronic acid (5.8 g, 30.3 mmol) andpalladium-tetrakis(triphenylphosphine) (1.5 g, 1.3 mmol) in aqueousNa₂CO₃ (2M, 32.5 mL, 64.9 mmol) and 1,4-dioxane (96.9 mL) was stirred at120° C. under a nitrogen atmosphere. After 48 hours, the reactionmixture was cooled and diluted with EtOAc. The resulting mixture waswashed with water (2×) and the organic layer was then dried over Na₂SO₄and concentrated in vacuo. The residue was purified (FCC, SiO₂,n-heptane/EtOAc, 0-50%) to afford a yellowish solid. The solid wastriturated with Et₂O to provide the title compound (2.1 g, 8.0 mmol,31.6%). MS (ESI): mass calcd. for C₁₃H₈F₃N₃, 263.1; m/z found, 264.1[M+H]⁺.

Intermediate 43: 6-(4-Fluorophenyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 42using (4-fluorophenyl)boronic acid instead of3-(trifluoromethyl)phenylboronic acid. MS (ESI): mass calcd forC₁₂H₈FN₃, 213.1; m/z found, 214.1 [M+H]⁺.

Intermediate 44:2-(6-(3-(Trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetohydrazide

Step A.2-(6-(3-(Trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)aceticacid. Sodium hydride (60% dispersion in mineral oil, 387.5 mg, 9.7 mmol)was added to a stirred solution of6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate42, 850 mg, 3.2 mmol) in DMF (20 mL) at 0° C., and the reaction mixturewas stirred at 0° C. for 10 minutes. Ethyl bromoacetate (0.54 mL, 4.8mmol) was then added and the reaction mixture was allowed to warm toroom temperature and stirred for 16 h. Aqueous potassium hydroxide (1M,16.1 mL, 16.1 mmol) was added and the reaction mixture stirred for 1hour. The reaction mixture was then concentrated and the residue wastaken up in water and washed with EtOAc. The aqueous layer was acidifiedwith 1M HCl and a precipitate forms. The solid was collected byfiltration and washed with water then dried. Trituration of the solidwith Et₂O provided the title compound (630 mg, 2.0 mmol, 60.7%). MS(ESI): mass calcd. for C₁₅H₁₀F₃N₃O₂, 321.1; m/z found, 322.2 [M+H]⁺.

Step B.2-(6-(3-(Trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetylchloride. A mixture of2-(6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)aceticacid (235 mg, 0.7 mmol) and thionyl chloride (5 mL, 68.9 mmol) wasstirred at 75° C. for 1 hour. The reaction mixture was then concentratedunder vacuum to provide the title compound (134 mg, 0.4 mmol, 53.9%)that was used directly in the following step.

Step C.2-(6-(3-(Trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetohydrazide.A solution of2-(6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetylchloride (Intermediate 5, 134 mg, 0.4 mmol) in hydrazine hydrate (5 mL)was stirred at rt for 30 min. The reaction mixture was then concentratedto afford the title compound that was used without purification. (138mg, 0.4 mmol). MS (ESI): mass calcd. for C₁₅H₁₂F₃N₅O, 335.1; m/z found,336.3 [M+H]⁺.

Intermediate 45:2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetohydrazide

To ethyl2-(6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetate(Step A, Intermediate 37, 217.3 mg, 0.622 mmol) stirring in EtOH (3 mL)was added hydrazine hydrate (0.36 mL, 7.263 mmol). The reaction mixturewas warmed to 70° C. until all solid had dissolved, then was removedfrom the heat, the stir bar was removed, and the mixture was left tocool to rt. The resulting slurry was filtered after standing for 3 daysat rt to afford the title compound as a white solid (140 mg, 66%). MS(ESI): mass calcd. for C₁₅H₁₂F₃N₅O, 335.1; m/z found, 336.1 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.80 (s, 1H), 8.38-8.32 (m, 1H), 8.26 (d, J=1.0Hz, 1H), 8.04-7.87 (m, 2H), 7.47-7.32 (m, 1H), 7.25-6.87 (m, 1H), 5.21(s, 2H).

Intermediate 46:6-Bromo-1-((2-methylpyrimidin-5-yl)methyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate44, Step A, using 6-bromo-1H-pyrazolo[4,3-b]pyridine and5-(chloromethyl)-2-methylpyrimidinehydrochloride. MS (ESI): mass calcd.for C₁₁H₈BrFN₅, 289.0; m/z found, 290.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 9.19-9.15 (m, 1H), 8.73-8.70 (m, 1H), 8.65-8.62 (m, 1H),8.42-8.39 (m, 1H), 7.70-7.65 (m, 1H), 7.52-7.47 (m, 1H), 6.02 (s, 2H).

Intermediate 47:6-Bromo-1-((2-methylpyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate44, Step A, using 6-bromo-1H-pyrazolo[4,3-b]pyridine and3-(chloromethyl)-2-methylpyridine. MS (ESI): mass calcd. for C₁₃H₁₁BrN₄,302.0; m/z found, 303.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.70-8.68(m, 1H), 8.64-8.62 (m, 1H), 8.42-8.41 (m, 1H), 8.37-8.34 (m, 1H),7.16-7.12 (m, 1H), 7.10-7.06 (m, 1H), 5.73 (s, 2H), 2.52 (s, 3H).

Intermediate 48:6-Bromo-1-(pyridazin-3-ylmethyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate44, Step A, using 6-bromo-1H-pyrazolo[4,3-b]pyridine and3-(chloromethyl)pyridazine hydrochloride. MS (ESI): mass calcd. forC₁₁H₈BrFN₅, 289.0; m/z found, 290.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ9.19-9.15 (m, 1H), 8.73-8.70 (m, 1H), 8.65-8.62 (m, 1H), 8.42-8.39 (m,1H), 7.70-7.65 (m, 1H), 7.52-7.47 (m, 1H), 6.02 (s, 2H).

Intermediate 49:6-Bromo-1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate44, Step A, using 6-bromo-1H-pyrazolo[4,3-b]pyridine and5-(chloromethyl)-2-fluoropyridine. MS (ESI): mass calcd. for C₁₂H₈BrFN₄,306.0; m/z found, 306.9 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.80-8.78(m, 1H), 8.62-8.61 (m, 1H), 8.40-8.38 (m, 1H), 8.31-8.28 (m, 1H), 7.89(td, J=8.2, 2.6 Hz, 1H), 7.15 (dd, J=8.5, 2.8 Hz, 1H), 5.72 (s, 2H).

Intermediate 50:6-Bromo-1-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate44, Step A, using 6-bromo-1H-pyrazolo[4,3-b]pyridine and3-(chloromethyl)pyridine hydrochloride. MS (ESI): mass calcd. forC₁₂H₉BrN₄, 288.0; m/z found, 289.0 [M+H]⁺.

Intermediate 51:6-Bromo-1-((5-methylpyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate44, Step A, using 6-bromo-1H-pyrazolo[4,3-b]pyridine and3-(chloromethyl)-5-methylpyridine hydrochloride. MS (ESI): mass calcd.for C₁₃H₁₁BrN₄, 302.0; m/z found, 303.0 [M+H]⁺.

Intermediate 52:6-Bromo-1-((4-methylpyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate44, Step A, using 6-bromo-1H-pyrazolo[4,3-b]pyridine and3-(chloromethyl)-4-methylpyridine hydrochloride. MS (ESI): mass calcd.for C₁₃H₁₁BrN₄, 302.0; m/z found, 303.0 [M+H]⁺.

Intermediate 53:6-Bromo-1-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate44, Step A, using 6-bromo-1H-pyrazolo[4,3-b]pyridine and2-(chloromethyl)pyridine hydrochloride. MS (ESI): mass calcd. forC₁₂H₉BrFN₄, 288.0; m/z found, 288.9 [M+H]⁺.

Intermediate 54:6-Bromo-1-((5-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Intermediate44, Step A, using 6-bromo-1H-pyrazolo[4,3-b]pyridine and3-(chloromethyl)-5-fluoropyridine hydrochloride. MS (ESI): mass calcd.for C₁₂H₈BrFN₄, 306.0; m/z found, 307.0 [M+H]⁺.

Intermediate 55:5-((6-Bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-3-methyl-1,2,4-oxadiazole

The title compound was prepared in a manner analogous to Intermediate44, Step A, using 6-bromo-1H-pyrazolo[4,3-b]pyridine and5-(chloromethyl)-3-methyl-1,2,4-oxadiazole. MS (ESI): mass calcd. forC₁₀H₈BrN₅O, 292.9; m/z found, 294.0 [M+H]⁺.

Intermediate 56:2-(3-(Difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

A solution of 4-bromo-2-(difluoromethyl)-1-fluorobenzene (20 g, 88.9mmol), bis(pinacolato)diboron (24.8 g, 97.8 mmol), potassium acetate(26.2 g, 267 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (3.12 g,4.44 mmol) in 1,4-dioxane (400 mL) was purged with N₂, and the reactionmixture was stirred at 90° C. overnight. Upon completion, the reactionmixture was cooled to room temperature, filtered through Celite®, andrinsed with EtOAc. The filtrate was washed with water and brine. Thecombined organics were dried with Na₂SO₄, filtered and concentrated toyield a clear oil (22.1 g, 81.0 mmol, 91%), which solidified uponstanding. ¹H NMR (400 MHz, Chloroform-d) δ 8.12-8.00 (m, 1H), 7.96-7.85(m, 1H), 7.17-7.06 (m, 1H), 6.88 (t, J=54.9 Hz, 1H), 1.35 (s, 12H). MS(ESI): mass calcd. for C₁₃H₁₆BF₃O₂, 272.1; m/z found, 273.0 [M+H]⁺.

Intermediate 57:2-(3-(1,1-Difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step A: 4-Bromo-2-(1,1-difluoroethyl)-1-fluorobenzene. In a round bottomflask, a mixture of 1-(5-bromo-2-fluorophenyl)-1-ethanone (2.5 g, 11.5mmol) and DAST (1.9 mL, 14.4 mmol) was heated at 60° C. for 16 h. Then asat. aq. solution of NaHCO₃ was slowly added at 0° C. and extracted withDCM. The organic layers were combined, dried over MgSO₄, filtered, andpartially concentrated (product is volatile). Purification (FCC, SiO₂,100% DCM) afforded the title compound (3 g, 7.5 mmol, purity 60%, 65%)as a brown oil. ¹H NMR (300 MHz, CDCl₃) δ 7.73-7.61 (m, 1H), 7.60-7.48(m, 1H), 7.02 (t, J=9.4 Hz, 1H), 1.98 (t, J=18.6 Hz, 3H).

Step B:2-(3-(1,1-Difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.In a round bottom flask, bis(pinacolato)diboron (2.87 g, 11.3 mmol, 1.5equiv), potassium acetate (2.22 g, 22.6 mmol, 3 equiv), and[1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium(II) (615 mg,0.75 mmol, 0.1 equiv) were added to a solution of4-bromo-2-(1,1-difluoroethyl)-1-fluorobenzene (3 g, 7.5 mmol, 1 equiv)in dry 1,4-dioxane (40 mL). The mixture was purged with nitrogen andstirred at 90° C. for 16 h. Then, a sat. aq. solution of NaHCO₃ wasadded and the mixture was extracted with EtOAc. The combined organicswere dried with MgSO₄, filtered and concentrated to yield a brown oil(2.15 g, 7.53 mmol), which was used in the next step without furtherpurification. MS (ESI): mass calcd. for C₁₄H₁₈BF₃O₂, 286.1; m/z found,287.1 [M+H]⁺.

Intermediate 58:2-(3-(Difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared in a manner analogous to Intermediate 56using 1-bromo-3-(difluoromethyl)benzene instead of4-bromo-2-(difluoromethyl)-1-fluorobenzene. No mass observed.

Intermediate 59:2-(3-(1,1-Difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared in a manner analogous to Intermediate 56using 1-bromo-3-(1,1-difluoroethyl)benzene instead of4-bromo-2-(difluoromethyl)-1-fluorobenzene. No mass observed.

Intermediate 60:2-(3-(Difluoromethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared in a manner analogous to Intermediate 56using 1-bromo-3-(difluoromethyl)-2-fluorobenzene instead of4-bromo-2-(difluoromethyl)-1-fluorobenzene. MS (ESI): mass calcd. forC₁₃H₁₆BF₃O₂, 272.1; m/z found, 273.2 [M+H]⁺.

Intermediate 61:2-(3-(Difluoromethoxy)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared in a manner analogous to Intermediate 56using 4-bromo-2-(difluoromethoxy)-1-fluorobenzene instead of4-bromo-2-(difluoromethyl)-1-fluorobenzene. MS (ESI): mass calcd. forC₁₃H₁₆BF₃O₃, 288.1; m/z found, 289.0 [M+H]⁺.

Intermediate 62:2-(4-Chloro-3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared in a manner analogous to Intermediate 56using 4-bromo-1-chloro-2-(difluoromethoxy)benzene instead of4-bromo-2-(difluoromethyl)-1-fluorobenzene. ¹H NMR (500 MHz, CDCl₃) δ7.62-7.56 (m, 2H), 7.44 (d, J=7.9 Hz, 1H), 6.56 (t, J=73.6 Hz, 1H), 1.34(s, 12H).

Intermediate 63:2-(4-Chloro-3-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared in a manner analogous to Intermediate 57using 5-bromo-2-chlorobenzaldehyde instead of1-(5-bromo-2-fluorophenyl)-1-ethanone in step A. MS (ESI): mass calcd.for C₁₃H₁₆BClF₂O₂, 288.1; m/z found, 289.1 [M+H]⁺.

Intermediate 64:2-(4-Chloro-3-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

The title compound was prepared in a manner analogous to Intermediate 57using 1-(5-bromo-2-chlorophenyl)ethan-1-one instead of1-(5-bromo-2-fluorophenyl)-1-ethanone in step A. ¹H NMR (500 MHz, CDCl₃)δ 8.02 (d, J=1.5 Hz, 1H), 7.79-7.71 (m, 1H), 7.47-7.39 (m, 1H), 2.03 (t,J=18.4 Hz, 3H), 1.34 (s, 12H).

Intermediate 65:2-(((tert-Butyldimethylsilyl)oxy)methyl)-5-(chloromethyl)-1,3,4-oxadiazole

Step A. 2-((tert-Butyldimethylsilyl)oxy)acetohydrazide: Ethyl2-((tert-butyldimethylsilyl)oxy)acetate (2.00 g, 9.16 mmol) andhydrazine hydrate (4.5 mL, 92 mmol) were dissolved in ethanol (50 mL).The reaction mixture was allowed to stand at room temperature overnightand then concentrated. The oil thus obtained (1.81 g, 8.86 mmol, 97%yield) was used directly in the next step without further purification.MS (ESI): mass calcd. for C₁₀H₂₂O₃Si, 204.1; m/z found, 205.2 [M+H]⁺.

Step B. Ethyl2-(2-(2-((tert-butyldimethylsilyl)oxy)acetyl)hydrazinyl)-2-oxoacetate: Asolution of 2-((tert-butyldimethylsilyl)oxy)acetohydrazide (1.81 g, 8.86mmol) and triethylamine (2.5 mL, 18 mmol) were dissolved in dry DCM (50mL) and the reaction mixture was cooled to 0° C. Monoethyl oxalylchloride (1.0 mL, 8.9 mmol) was added dropwise, and the reaction mixturewas stirred at 0° C. for one hour. The mixture was partitioned betweenDCM and water, the aqueous layer was extracted 3× with DCM, the combinedorganics were dried (MgSO₄), concentrated, and the crude product (3.14g, 10.3 mmol, >100% measured yield) was used directly in subsequenttransformations. MS (ESI): mass calcd. for C₁₂H₂₄N₂O₅Si, 304.1; m/zfound, 305.2 [M+H]⁺.

Step C. Ethyl5-(((tert-butyldimethylsilyl)oxy)methyl)-1,3,4-oxadiazole-2-carboxylate:Ethyl2-(2-(2-((tert-butyldimethylsilyl)oxy)acetyl)hydrazinyl)-2-oxoacetate(3.14 g, 10.3 mmol) and triethylamine (1.7 mL, 12 mmol) were dissolvedin dry DCM (100 mL). Tosyl chloride (1.97 g, 10.3 mmol) was added in oneportion, and the reaction mixture was stirred at r.t. overnight. Themixture was then diluted with water, the aqueous layer was extractedwith DCM, and the combined organics were concentrated and purified onsilica gel (0-100% ethyl acetate/hexanes) to obtain 1.87 g (6.53 mmol,63% yield) of the desired product. MS (ESI): mass calcd. forC₁₂H₂₂N₂O₄Si, 286.1; m/z found, 287.2 [M+H]⁺.

Step D.(5-(((tert-Butyldimethylsilyl)oxy)methyl)-1,3,4-oxadiazol-2-yl)methanol:A solution of ethyl5-(((tert-butyldimethylsilyl)oxy)methyl)-1,3,4-oxadiazole-2-carboxylate(1.87 g, 6.53 mmol) was dissolved in methanol (40 mL) and the reactionmixture was cooled to 0° C. Sodium borohydride (988 mg, 26.1 mmol) wasadded portion wise and the reaction mixture was stirred at r.t. for 2hours, concentrated to remove volatiles, and partitioned between DCM andwater. The aqueous layer was extracted 2× with DCM and the combinedorganics were concentrated and purified on silica gel (0-100% ethylacetate/hexanes) to obtain 1.18 g (4.83 mmol, 74% yield) of the desiredproduct. MS (ESI): mass calcd. for C₁₀H₂₀N₂O₃Si, 244.1; m/z found, 245.2[M+H]⁺.

Step E.2-(((tert-butyldimethylsilyl)oxy)methyl)-5-(chloromethyl)-1,3,4-oxadiazole:(5-(((tert-Butyldimethylsilyl)oxy)methyl)-1,3,4-oxadiazol-2-yl)methanol(400 mg, 1.64 mmol) and triethylamine (0.68 mL, 4.9 mmol) were dissolvedin dry DCM (10 mL). Thionyl chloride (0.24 mL, 3.3 mmol) was addeddropwise and the reaction mixture was stirred overnight at r.t. Themixture was partitioned between DCM and sat. aq. Na₂CO₃, the aqueouslayer was extracted with DCM, and the combined organics wereconcentrated and purified on silica gel (0-100% ethyl acetate/hexanes)to obtain 182 mg (0.693 mmol, 42% yield) of the desired product. MS(ESI): mass calcd. for C₁₀H₁₉ClN₂O₂Si, 262.1; m/z found, 263.2 [M+H]⁺.

Intermediate 66:3-Bromo-6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine

A suspension of6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 25), 1.0 g, 3.8 mmol) and trimethylphenylammoniumtribromide (2.9 g, 7.6 mmol) was stirred in ACN (62.5 mL) at roomtemperature. After 3 days, a saturated aqueous solution of sodiumbicarbonate (120 mL) was added to the reaction mixture. The resultingmixture was extracted with EtOAc (3×150 mL). The combined organics weredried over MgSO₄, filtered and evaporated. Purification (FCC, SiO₂,0-99% EtOAc in hexanes) afforded the title compound (463 mg, 36%). MS(ESI): mass calcd. for C₁₃H₇BrF₃N₃, 341.0; m/z found, 342.0 [M+H]⁺. ¹HNMR (600 MHz, DMSO-d₆) δ 13.84 (s, 1H), 8.90 (d, J=1.9 Hz, 1H), 8.31 (d,J=1.9 Hz, 1H), 8.10-8.05 (m, 2H), 7.59-7.54 (m, 1H), 7.27 (t, J=54.1 Hz,1H).

Intermediate 67:2-(3-(Difluoromethyl)-4-fluorophenyl-1,2,3,4,5,6-¹³C₆)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Step A. 5-Bromo-2-fluorobenzaldehyde-1,2,3,4,5,6-¹³C₆. To a solution ofdi-isopropyl amine (0.58 mL, 4.15 mmol) in THE (10 mL) at −78° C. wasadded n-BuLi (1.59 mL, 2.5 M, 3.97 mmol) dropwise. The solution wasstirred at −78° C. for 30 min. To the LDA solution was added1-bromo-4-fluorobenzene-1,2,3,4,5,6-¹³C₆ (600 mgs, 3.32 mmol) in 1 mL ofTHF. The resulting solution was stirred at −78° C. for 30 min. DMF wasthen added and the solution was further stirred at −78° C. for anadditional 1 h. The reaction mixture was quenched with 2M H₂SO₄ (10 mL)and allowed to warm to rt. The mixture was extracted with Et₂O (5 mL,×3) and the combined organic extracts were washed with brine (5 mL, ×3)and dried over MgSO₄. Filtration and concentration provided the titlecompound (0.856 g, 2.28 mmol) of colorless oil.

Step B.2-(3-(Difluoromethyl)-4-fluorophenyl-1,2,3,4,5,6-¹³C₆)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.The title compound was prepared in a manner analogous to Intermediate 57using 5-bromo-2-fluorobenzaldehyde-1,2,3,4,5,6-¹³C₆ from Step A. MS(ESI): mass calcd. for C₇ ¹³C₆H₁₆BF₃O₂, 278.1; m/z found, 279.1 [M+H]⁺.

Intermediate 68:1-((6-Bromopyridin-3-yl)methyl)-6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine

To a solution of Intermediate 25 (40 mg, 0.15 mmol) in 2 mL of DMF wasadded NaH (60% dispersion in mineral oil, 18 mg, 0.45 mmol). Thismixture was stirred at rt for 20 min. The mixture was cooled to −40° C.and 2-bromo-5-(bromomethyl)pyridine was added (38.1 mg, 0.15 mml). Thereaction mixture was stirred at −40° C. for 20 min then was quenched byadding 3 g of dry ice. The reaction mixture was warmed to rt and dilutedwith EtOAc (30 mL). This was then washed with water (3×30 mL), driedover Na₂SO₄ and concentrated. Purification (FCC, SiO₂, 0 to 100%EtOAc/hexanes) afforded the title compound (45 mg, 0.10 mmol, 68%). MS(ESI): mass calcd. for C₁₉H₁₂BrF₃N₄, 432.0; m/z found, 455.1 [M+Na]⁺. ¹HNMR (400 MHz, CDCl₃) δ 8.84 (d, J=1.8 Hz, 1H), 8.40 (t, J=1.8 Hz, 2H),7.87-7.82 (m, 2H), 7.76-7.71 (m, 1H), 7.50-7.47 (m, 1H), 7.45-7.42 (m,1H), 7.36-7.31 (m, 1H), 7.02 (t, J=54.8 Hz, 1H), 5.66 (s, 2H).

Example 1:1-(Pyrimidin-2-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

6-(3-(Trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate42, 100 mg, 0.4 mmol) was added to a suspension of NaH (60% dispersionin mineral oil, 36.4 mg, 0.9 mmol) in DMF (4.0 mL) at room temperatureunder a nitrogen atmosphere. After 10 min, 2-(chloromethyl)pyrimidinehydrochloride (87.8 mg, 0.5 mmol) was added and the reaction mixture washeated to 75° C. After 3 h, the reaction mixture was cooled to roomtemperature and water was added. The resulting precipitate was collectedby filtration, rinsed with water, and dried under vacuum to providetitle compound (72.8 mg, 0.2 mmol, 53.9%). MS (ESI): mass calcd. forC₁₈H₁₂F₃N₅, 355.1; m/z found, 356.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.97 (d, J=1.9 Hz, 1H), 8.73 (d, J=4.9 Hz, 2H), 8.67-8.65 (m, 1H),8.39-8.37 (m, 1H), 8.18-8.14 (m, 2H), 7.83-7.74 (m, 2H), 7.42 (t, J=4.9Hz, 1H), 6.02 (s, 2H).

Example 2:1-[(5-Bromo-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 1,using 3-bromo-5-(chloromethyl)pyridine instead of2-(chloromethyl)pyrimidine hydrochloride. MS (ESI): mass calcd. forC₁₉H₁₂BrF₃N₄, 432.0; m/z found, 432.9 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 8.97 (d, J=1.9 Hz, 1H), 8.79-8.77 (m, 1H), 8.65 (d, J=2.2 Hz, 1H),8.59-8.57 (m, 1H), 8.45-8.43 (m, 1H), 8.21-8.16 (m, 2H), 8.02 (t, J=2.1Hz, 1H), 7.85-7.78 (m, 2H), 5.82 (s, 2H).

Example 3:5-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile

A microwave vial was charged with1-[(5-bromo-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine(Example 2, 80 mg, 0.2 mmol), zinc cyanide (43.3 mg, 0.4 mmol),[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (9.5 mg, 0.01 mmol) and DMA (1.5 mL). The microwavevial was purged with nitrogen and capped. The reaction mixture washeated to 150° C. under microwave irradiation for 30 min. The mixturewas then purified by reverse phase basic HPLC (Method A) to providetitle compound (28 mg, 40%). MS (ESI): mass calcd. for C₂₀H₁₂F₃N₅,379.1; m/z found, 380.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ 8.98-8.95(m, 2H), 8.87 (d, J=2.1 Hz, 1H), 8.77-8.75 (m, 1H), 8.45-8.43 (m, 1H),8.26 (t, J=2.1 Hz, 1H), 8.21-8.16 (m, 2H), 7.86-7.77 (m, 2H), 5.88 (s,2H).

Example 4:1-[(2-Methylpyrimidin-5-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridinetrifluoroacetate Salt

A mixture of6-bromo-1-((2-methylpyrimidin-5-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 46, 60 mg, 0.2 mmol), (3-(trifluoromethyl)phenyl)boronicacid (56 mg, 0.3 mmol), Cs₂CO₃ (129 mg, 0.4 mmol), and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (10 mg, 0.01 mmol), in 1,4-dioxane (1.8 mL) washeated to 90° C. After completion, the reaction mixture was concentratedunder vacuum and the residue purified by reverse phase HPLC (Method C)to provide title compound (42 mg, 0.09 mmol, 44%). MS (ESI): mass calcd.for C₁₉H₁₄F₃N₅, 369.1; m/z found, 370.0 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.96 (d, J=2.0 Hz, 1H), 8.80-8.78 (m, 1H), 8.73 (s, 2H),8.43-8.40 (m, 1H), 8.22-8.16 (m, 2H), 7.87-7.77 (m, 2H), 5.79 (s, 2H),2.58 (s, 3H).

Example 5:1-(Pyrazin-2-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridinedihydrochloride Salt

Di-tert-butyl azodicarboxylate (157.4 mg, 0.7 mmol) was added to asolution of 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 42, 150 mg, 0.6 mmol), 2-pyrazinylmethanol (75.3 mg, 0.7mmol) and triphenylphosphine (179.4 mg, 0.7 mmol) in THF (5 mL) at 0° C.After 21 hours, the solvent was removed and the residue taken up in DCMand washed with water then dried over Na₂SO₄ and concentrated undervacuum. The residue was purified (FCC, SiO₂, 0-10% DCM/MeOH) to affordthe desired product with trace impurities. The material was subjected toion exchange chromatography using an ISOLUTE SCX2 cartridge eluting withMeOH followed by 7N NH₃/MeOH. The desired fractions were collected andconcentrated. The material was then purified by reverse phase HPLC(Method A). The desired fractions were concentrated under vacuum and theresidue was treated with HCl in MeOH for 5 min, the solvent was removedunder vacuum to provide the title product (33 mg, 0.08 mmol, 13.5%). MS(ESI): mass calcd. for C₁₈H₁₂F₃N₅, 355.1; m/z found, 356.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d 6) δ 9.05 (s, 1H), 8.84 (s, 2H), 8.72-8.54 (m, 4H),8.47 (s, 1H), 8.30-8.10 (m, 2H), 7.95-7.71 (m, 2H), 6.04 (s, 2H).

Example 6:1-(Pyrimidin-4-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridinehydrochloride Salt

Di-tert-butyl azodicarboxylate (157.5 mg, 0.7 mmol) was added to asolution of 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 42, 150 mg, 0.6 mmol), 4-(hydroxymethyl)pyrimidine (75.3mg, 0.7 mmol) and polymer bound triphenylphosphine (323.0 mg, 0.7 mmol)in THE at 0° C. The cold bath was removed and the reaction mixturestirred at rt. After 16 hours additional 4-(hydroxymethyl)pyrimidine(37.7 mg, 0.3 mmol), di-tert-butyl azodicarboxylate (78.7 mg, 0.7 mmol)and polymer bound triphenylphosphine (161.5 mg, 0.3 mmol) were added tothe reaction mixture. After 2 hours, the reaction mixture was thenheated at 50° C. Upon completion, the mixture was filtered and thefiltrate was concentrated. The residue was partitioned between water/DCMand the layers separated. The aqueous layer was extracted with DCM andthe combined organics were dried over Na₂SO₄ and concentrated. Theresidue was purified (FCC, SiO₂, 0-10% MeOH in DCM) to afford thedesired product with trace impurities. The material was further purified(FCC, SiO₂, 50-100% EtOAc in heptane), the desired fractions werecollected and concentrated, and the residue was treated with HCl in MeOHfor 5 min. The solvent was removed under vacuum to provide the titlecompound (58 mg, 0.15 mmol, 26.0%). MS (ESI): mass calcd. forC₁₈H₁₂F₃N₅, 355.1; m/z found, 356.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d 6) δ9.03 (d, J=1.16 Hz, 1H), 8.95 (d, J=1.85 Hz, 1H), 8.71-8.61 (m, 2H),8.40 (d, J=0.92 Hz, 1H), 8.12-8.07 (m, 2H), 7.78-7.66 (m, 2H), 5.89 (s,2H) 7.07 (dd, J=5.20, 1.27 Hz, 1H).

Example 7:2-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-oxadiazole

Step A:N′-Formyl-2-(6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetohydrazide.A solution of2-(6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetohydrazide(Intermediate 44, 68 mg, 0.2 mmol) in triethyl orthoformate (4 mL) wasstirred at 140° C. After 22 hours the volatiles were removed undervacuum and the crude product was used in the next step without furtherpurification.

Step B:2-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-oxadiazole.N′-Formyl-2-(6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetohydrazidewas dissolved in toluene (4 mL) and p-toluenesulfonic acid monohydrate(3.9 mg, 0.02 mmol) was added. The reaction mixture was then heated to110° C. After 24 hours, the solvent was removed and the residue waspurified (FCC, SiO₂, 0-10% EtOAc in heptane) to provide the titlecompound (8 mg, 0.02 mmol, 11.4%). MS (ESI): mass calcd. forC₁₆H₁₀F₃N₅O, 345.1; m/z found, 346.1 [M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.87 (d, J=1.8 Hz, 1H), 8.39 (s, 1H), 8.36 (d, J=1.2 Hz, 1H), 8.03 (dd,J=0.9, 1.8 Hz, 1H), 7.88 (s, 1H), 7.83 (d, J=7.6 Hz, 1H), 7.76-7.70 (m,1H), 7.69-7.62 (m, 1H), 5.93 (s, 2H)

Example 8:2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyloxazole

To 6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 25, 35 mg, 0.133 mmol) stirring in DMF (1 mL) at rt wasadded Cs₂CO₃ (129.97 mg, 0.399 mmol) followed by2-(chloromethyl)-5-methyl-1,3-oxazole (26.24 mg, 0.199 mmol). Thereaction was stirred at rt for 3 h, then filtered through a 0.45 μMsyringe filter and purified by prep HPLC (Method A) to afford the titlecompound (21.1 mg, 44%). MS (ESI): mass calcd. for C₁₈H₁₃F₃N₄O, 358.1;m/z found, 359.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.84 (d, J=1.9 Hz,1H), 8.45 (dd, J=1.9, 1.0 Hz, 1H), 8.28 (d, J=1.0 Hz, 1H), 8.03-7.93 (m,2H), 7.48-7.37 (m, 1H), 7.09 (t, J=54.6 Hz, 1H), 6.76 (d, J=1.3 Hz, 1H),5.83 (s, 2H), 2.27 (d, J=1.2 Hz, 3H).

Example 9:2-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyloxazole

To a microwave vial was added2-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyloxazole(Intermediate 22, 25 mg, 0.0853 mmol),(2,4-difluoro-3-methylphenyl)boronic acid (17.597 mg, 0.102 mmol),Cs₂CO₃ (83.366 mg, 0.256 mmol), RuPhos Pd G3 (3.567 mg, 0.00426 mmol),and 1,4-dioxane (1 mL). The vial was purged with N₂, sealed, and stirredat 80° C. overnight. The reaction was removed from the heat, cooled tort, then filtered through a 0.45 μM syringe filter. Purification (MethodA) afforded the title compound (13.0 mg, 45%). MS (ESI): mass calcd. forC₁₈H₁₄F₂N₄O, 340.1; m/z found, 341.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.69 (s, 1H), 8.34-8.23 (m, 2H), 7.56-7.41 (m, 1H), 7.19-7.03 (m, 1H),6.75 (d, J=1.2 Hz, 1H), 5.80 (s, 2H), 2.34-2.20 (m, 6H).

Example 10:2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole

2-((6-Bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole(Intermediate 19, 445.6 mg, 1.515 mmol),2-(3-(difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(541.8 mg, 1.991 mmol), Na₂CO₃ (319.3 mg, 3.013 mmol),(1,1′-bis(diphenylphosphino)ferrocene)dichloropalladium(II) (55.1 mg,0.0748 mmol), 1,4-dioxane (5 mL), and water (1.25 mL) were placed in amicrowave vial. The vial was sealed and stirred at 100° C. for 1 h. Thereaction mixture was cooled to rt, diluted with EtOAc and water, thenthe layers were separated and the aqueous layer was extracted with EtOAc(×3). The combined organic layers were dried over Na₂SO₄ andconcentrated under reduced pressure. The residue was purified (FCC,SiO₂, 0-8% MeOH in DCM), then re-purified (FCC, SiO₂, 50-100% EtOAc inhexanes) to afford the title compound (370 mg, 68%). MS (ESI): masscalcd. for C₁₇H₁₂F₃N₅O, 359.1; m/z found, 360.1 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 8.94 (d, J=1.9 Hz, 1H), 8.67-8.61 (m, 1H), 8.47-8.42 (m, 1H),8.12-8.05 (m, 2H), 7.64-7.54 (m, 1H), 7.31 (t, J=54.1 Hz, 1H), 6.10 (s,2H), 2.44 (s, 3H).

Example 11:6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridine

Step A.6-(3-(Difluoromethoxy)-4-fluorophenyl)-1-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridine.To a suspension of sodium hydride (60% in mineral oil, 12.0 mg, 0.300mmol) in DMF (500 μL) was added a solution of6-[3-(difluoromethoxy)-4-fluoro-phenyl]-1H-pyrazolo[4,3-b]pyridine(Intermediate 26, 80 mg, 0.287 mmol) in DMF (600 μL) at 0° C. underargon and the reaction was stirred at 0° C. for 30 min. To the reactionmixture was added a solution of4-(chloromethyl)-1-tetrahydropyran-2-yl-pyrazole (Intermediate 1, 60 mg,0.299 mmol) in DMF (500 μL) at 0° C. and the reaction mixture wasstirred at room temperature for 18 h. The reaction mixture was pouredinto water (10 mL) and extracted with EtOAc (3×5 mL). The combinedorganics were dried over MgSO₄, filtered and concentrated. Purification(FCC, SiO₂, 0 to 100% EtOAc in n-heptane) afforded the title compound(82 mg, 0.185 mmol, 64%) as a yellow oil. MS (ESI): mass calcd. forC₂₂H₂₀F₃N₅O₂, 443.2; m/z found, 444.2 [M+H]⁺.

Step B.6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridine.To6-(3-(difluoromethoxy)-4-fluorophenyl)-1-((1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(80 mg, 0.180 mmol) was added hydrogen chloride (4.90 M in 1,4-dioxane,3 mL, 14.7 mmol) and the reaction mixture was stirred at roomtemperature for 18 h. The reaction mixture was concentrated and theresidue was purified by preparative HPLC (METHOD E) to afford the titlecompound (32 mg, 0.089 mmol, 49%) as a white powder. MS (ESI): masscalcd. for C₁₇H₁₂F₃N₅O, 359.1; m/z found, 360.1 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 12.74 (br s, 1H), 8.92-8.83 (m, 1H), 8.54-8.47 (m, 1H), 8.33(s, 1H), 7.89-7.81 (m, 1H), 7.81-7.71 (m, 1H), 7.68-7.55 (m, 2H), 7.39(t, J=73.2 Hz, 1H), 6.17-6.09 (m, 1H), 5.71 (s, 2H).

Example 12:6-[3-(1,1-Difluoroethyl)phenyl]-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine

A mixture of 6-(3-(1,1-difluoroethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 29, 70 mg, 0.270 mmol), 3-(chloromethyl)pyridinehydrochloride (49 mg, 0.299 mmol) and Cs₂CO₃ (220 mg, 0.675 mmol) in dryDMF (1.4 mL) was stirred at 80° C. for 18 h. The reaction mixture waspoured into water (10 mL) and extracted with EtOAc (3×5 mL). Thecombined organics were dried over MgSO₄, filtered and concentrated.Purification (FCC, SiO₂, 0 to 5% MeOH in DCM) afforded the titlecompound (45 mg, 0.128 mmol, 47%) as a yellow oil. MS (ESI): mass calcd.for C₂₀H₁₆F₂N₄, 350.1; m/z found, 351.2 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.93 (d, J=1.9 Hz, 1H), 8.71-8.67 (m, 1H), 8.64-8.59 (m, 1H),8.49 (dd, J=4.8, 1.7 Hz, 1H), 8.42-8.39 (m, 1H), 8.01-7.92 (m, 2H),7.71-7.62 (m, 3H), 7.37-7.31 (m, 1H), 5.82 (s, 2H), 2.06 (t, J=18.9 Hz,3H).

Example 13:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-methyl-4H-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridine

To a suspension of2-(6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetohydrazide(Intermediate 45, 35 mg, 0.0857 mmol) and ethyl acetamidatehydrochloride (32 mg, 0.259 mmol) in ethanol (1.05 mL) was addedtriethylamine (72 μL, 0.516 mmol, 0.726 g/mL). The reaction mixture wasstirred at 70° C. for 1 h then cooled and evaporated to dryness. Theresidue was taken up in DCM (5 mL) and the organic layer was washed withwater (1×5 mL). The aqueous washing was extracted with DCM (2×5 mL) andthe combined organics were dried over Na₂SO₄, filtered and concentrated.Purification (FCC, SiO₂, 0 to 5% MeOH in DCM) afforded the titlecompound (13 mg, 0.036 mmol, 42%) as a white powder. MS (ESI): masscalcd. for C₁₇H₁₃F₃N₆, 358.1; m/z found, 359.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 13.50 (br s, 1H), 8.89 (d, J=2.0 Hz, 1H), 8.59-8.52 (m, 1H),8.37-8.27 (m, 1H), 8.12-8.02 (m, 2H), 7.62-7.54 (m, 1H), 7.30 (t, J=54.1Hz, 1H), 5.72 (s, 2H), 2.25 (s, 3H).

Example 14:1-[(3-Methyl-1H-pyrazol-5-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

A microwave vial was charged with1-[(2,5-dimethylpyrazol-3-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine(Example 37, 48 mg, 0.13 mmol) and pyridine hydrochloride (600 mg, 5.2mmol). The vial was flushed with N₂, sealed and heated to 190° C.overnight. The reaction mixture was cooled and methanol was added to themelt and the resulting residue was purified by prep HPLC (Method A) togive the title compound as a solid (10 mg, 22%). MS (ESI): mass calcd.for C₁₈H₁₄F₃N₅, 357.1; m/z found, 358.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃)δ 8.80-8.77 (m, 1H), 8.30-8.27 (m, 1H), 7.98-7.95 (m, 1H), 7.87-7.78 (m,2H), 7.71-7.59 (m, 2H), 5.97 (s, 1H), 5.63 (s, 2H), 2.25 (s, 3H).

Example 15:5-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-N-methyl-1,3,4-thiadiazol-2-amine

Step A.2-(2-(6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)acetyl)-N-methylhydrazine-1-carboxamide.To a solution of2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]aceticacid (Intermediate 40, 150 mg, 0.445 mmol) and triethylamine (186 μL,1.33 mmol, 0.726 g/mL) in DCM (4.2 mL) was added 3-amino-1-methylurea(48 mg, 0.539 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimidehydrochloride (102 mg, 0.532 mmol) and 1-hydroxybenzotriazole hydrate(82 mg, 0.535 mmol). The reaction mixture was stirred at roomtemperature for 18 h. The reaction mixture was diluted with DCM (10 mL)and washed with 20% Na₂CO₃ (1×10 mL). The aqueous layer was thenextracted with DCM (3×10 mL). The combined organics were dried overNa₂SO₄, filtered and concentrated to give the title compound (304 mg) asan off-white powder. MS (ESI): mass calcd. for C₁₇H₁₅F₃N₆O₃, 408.1; m/zfound, 409.1 [M+H]⁺.

Step B.5-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-N-methyl-1,3,4-thiadiazol-2-amine.A mixture of1-[[2-[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]amino]-3-methyl-urea(150 mg, 0.367 mmol) and2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane(Lawesson's reagent) (297 mg, 0.735 mmol) in toluene (3.75 mL) wasstirred at 105° C. for 20 h. The reaction mixture was concentrated, andthe residue was purified. Purification (FCC, SiO₂, 0 to 10% MeOH in DCM)afforded the title compound (15 mg, 0.037 mmol, 10%) as a white powder.MS (ESI): mass calcd. for C₁₇H₁₃F₃N₆OS, 406.1; m/z found, 407.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.92 (d, J=1.9 Hz, 1H), 8.62-8.58 (m, 1H),8.43 (d, J=1.0 Hz, 1H), 7.88-7.83 (m, 1H), 7.81-7.75 (m, 1H), 7.66-7.59(m, 1H), 7.61 (dd, J=10.5, 8.8 Hz, 1H), 7.39 (t, J=73.2 Hz, 1H), 5.98(s, 2H), 2.80 (d, J=4.8 Hz, 3H).

Example 16:5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazol-2-amine

Step A.[[2-[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]amino]urea.To a solution of2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]aceticacid (Intermediate 37, 1.50 g, 4.67 mmol) in DCM (40 mL) was addedsemicarbazide hydrochloride (625 mg, 5.60 mmol),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (1.07 g,5.58 mmol), 1-hydroxybenzotriazole hydrate (858 mg, 5.60 mmol) andtriethylamine (2.6 mL, 18.6 mmol) and the mixture was stirred at roomtemperature for 74 h. DMF (10 mL) was added and the reaction was stirredfor 45 h. Additional DMF was added (30 mL) and the reaction was stirredfor 24 h. The reaction mixture was concentrated to 40 mL under vacuumand stirred for an additional 24 h. The reaction mixture was thendiluted with dichloromethane (120 mL) and washed with 20% aq. Na₂CO₃(1×120 mL). The aqueous layer was then extracted with CHCl₃:2-propanol(3:1, 4×105 mL). The combined organic layers were concentrated. Theresidue was purified by preparative HPLC (Method E) to give the titlecompound (793 mg, 2.10 mmol, 45%) as a white powder. MS (ESI): masscalcd. for C₁₆H₁₃F₃N₆O₂, 378.1; m/z found, 379.1 [M+H]⁺.

Step B.5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazol-2-amine.A mixture of[[2-[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]acetyl]amino]urea(765 mg, 2.02 mmol) and 4-methoxyphenylthionophosphine sulfide dimer(Lawesson's reagent) (1.63 g, 4.04 mmol) in THE (23 mL) was stirred at100° C. for 2 h under argon and microwave irradiation. The reactionmixture was concentrated, and the residue was purified. Purification(FCC, SiO₂, 0 to 10% DCM/MeOH—NH₃), afforded the title compound. Furtherpurification by preparative HPLC (Method E) afforded the title compound(19 mg, 0.050 mmol, 2%) as a white powder. MS (ESI): mass calcd. forC₁₆H₁₁F₃N₆S, 376.1; m/z found, 377.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.92 (d, J=1.9 Hz, 1H), 8.66-8.61 (m, 1H), 8.44-8.40 (m, 1H), 8.12-8.05(m, 2H), 7.62-7.55 (m, 1H), 7.30 (t, J=54.2 Hz, 1H), 7.18 (br s, 2H),5.97 (s, 2H).

Also isolated from the reaction mixture was5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazol-2-ol(147 mg, 0.390 mmol, 19%) as a white powder. MS (ESI): mass calcd. forC₁₆H₁₀F₃N₆OS, 377.1; m/z found, 378.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆)δ 12.87 (br s, 1H), 8.98-8.88 (m, 1H), 8.67-8.58 (m, 1H), 8.51-8.40 (m,1H), 8.17-8.01 (m, 2H), 7.65-7.53 (m, 1H), 7.30 (t, J=54.1 Hz, 1H), 5.88(s, 2H).

Example 17:5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazol-2-ol

The title compound was also isolated from Example 16. MS (ESI): masscalcd. for C₁₆H₁₀F₃N₆OS, 377.1; m/z found, 378.1 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 12.87 (br s, 1H), 8.98-8.88 (m, 1H), 8.67-8.58 (m, 1H),8.51-8.40 (m, 1H), 8.17-8.01 (m, 2H), 7.65-7.53 (m, 1H), 7.30 (t, J=54.1Hz, 1H), 5.88 (s, 2H).

Example 18:5-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazol-2-amine

The title compound was prepared in a manner analogous to Example 16using2-(6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)aceticacid (Intermediate 40) in Step A. MS (ESI): mass calcd. forC₁₆H₁₁F₃N₆OS, 392.1; m/z found, 393.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆)δ 8.92 (d, J=2.0 Hz, 1H), 8.62-8.57 (m, 1H), 8.43 (d, J=1.0 Hz, 1H),7.86 (dd, J=7.6, 2.3 Hz, 1H), 7.80-7.75 (m, 1H), 7.61 (dd, J=10.5, 8.6Hz, 1H), 7.38 (t, J=73.2 Hz, 1H), 7.18 (s, 2H), 5.96 (s, 2H).

Example 19:N-(5-((6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-1,3,4-thiadiazol-2-yl)acetamide

To a solution of5-[[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazol-2-amine(Example 18, 18.0 mg, 0.0459 mmol) in toluene (840 μL) was added aceticanhydride (9 μL, 0.0954 mmol) and the reaction mixture was stirred at60° C. for 13 h. The reaction mixture was washed with 10% aq. Na₂CO₃(1×5 mL) and the aqueous layer was extracted with EtOAc (1×5 mL). Thecombined organics were dried over Na₂SO₄, filtered and concentrated.Purification (FCC, SiO₂, 0 to 10% MeOH in DCM) afforded the titlecompound (18 mg, 0.041 mmol, 89%) as a white powder. MS (ESI): masscalcd. for C₁₈H₁₃F₃N₆O₂S, 434.1; m/z found, 435.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 12.51 (br s, 1H), 8.93 (d, J=2.0 Hz, 1H), 8.68-8.63 (m,1H), 8.46 (d, J=1.0 Hz, 1H), 7.86 (dd, J=7.5, 2.3 Hz, 1H), 7.82-7.74 (m,1H), 7.61 (dd, J=10.5, 8.6 Hz, 1H), 7.38 (t, J=73.2 Hz, 1H), 6.16 (s,2H), 2.13 (s, 3H)

Example 20:3-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,2,4-oxadiazole

A mixture of 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 42, 200 mg, 0.76 mmol), 3-(chloromethyl)-1,2,4-oxadiazole(0.13 mL, 1.5 mmol) and Cs₂CO₃ (495 mg, 1.5 mmol) in DMF (1.5 mL) werestirred at 50° C. for 6 h. The mixture was cooled, the solids filteredoff, and the solvent evaporated. The residue was purified (FCC, SiO₂,0-6% MeOH in DCM) and the desired fractions were collected. The materialwas further purified by reverse phase HPLC (Method A) to provide thetitle compound (31 mg, 0.09 mmol, 11.8%). MS (ESI): mass calcd. forC₁₆H₁₀F₃N₅O, 345.1; m/z found, 346.1[M+H]⁺. ¹H NMR (400 MHz, CDCl₃) δ8.85 (d, J=1.85 Hz, 1H), 8.71 (s, 1H), 8.36 (d, J=0.69 Hz, 1H), 8.03 (s,1H), 7.89 (s, 1H), 7.84 (d, J=7.63 Hz, 1H), 7.76-7.69 (m, 1H), 7.69-7.61(m, 1H), 5.85 (s, 2H).

Example 21:1-Benzyl-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridinehydrochloride Salt

The title compound was prepared in a manner analogous to Example 8,using 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 42) and benzyl bromide. MS (ESI): mass calcd. forC₂₀H₁₄F₃N₃, 353.1; m/z found, 354.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.97 (d, J=1.85 Hz, 1H), 8.75 (dd, J=1.97, 1.04 Hz, 1H), 8.41 (d, J=0.92Hz, 1H), 8.25-8.05 (m, 2H), 7.97-7.68 (m, 2H), 7.46-7.06 (m, 5H), 5.79(s, 2H).

Example 22:1-[(3-Fluorophenyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridinehydrochloride Salt

The title compound was prepared in a manner analogous to Example 8,using 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 42) and 3-fluorobenzyl bromide. MS (ESI): mass calcd. forC₂₀H₁₃F₄N₃, 371.1; m/z found, 372.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.98 (d, J=2.08 Hz, 1H), 8.76 (dd, J=1.85, 0.92 Hz, 1H), 8.44 (d, J=0.92Hz, 1H), 8.28-8.09 (m, 2H), 7.93-7.71 (m, 2H), 7.51-7.29 (m, 1H),7.25-6.95 (m, 3H), 5.81 (s, 2H).

Example 23:3-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]benzonitrile

The title compound was prepared in a manner analogous to Example 8,using 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 42) and 3-cyanobenzyl bromide. MS (ESI): mass calcd. forC₂₁H₁₃F₃N₄, 378.1; m/z found, 379.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.86 (d, J=2.02 Hz, 1H), 8.39 (d, J=1.16 Hz, 1H), 7.85 (s, 1H),7.75-7.82 (m, 2H), 7.69-7.74 (m, 1H), 7.56-7.69 (m, 2H), 7.40-7.52 (m,3H), 5.70 (s, 2H).

Example 24:1-[(4-Methoxyphenyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridinehydrochloride Salt

The title compound was prepared in a manner analogous to Example 8,using 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 42) and 4-methoxybenzyl chloride. MS (ESI): mass calcd.for C₂₁H₁₆F₃N₃₀, 383.1; m/z found, 384.3 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ 8.95 (d, J=2.08 Hz, 1H), 8.74 (dd, J=1.85, 0.92 Hz, 1H), 8.38 (d,J=0.92 Hz, 1H), 8.10-8.26 (m, 2H), 7.72-7.96 (m, 2H), 7.18-7.42 (m, 2H),6.77-6.97 (m, 2H), 5.70 (s, 2H), 3.70 (s, 4H).

Example 25:6-[3-(Trifluoromethyl)phenyl]-1-[[4-(trifluoromethyl)phenyl]methyl]pyrazolo[4,3-b]pyridinehydrochloride Salt

The title compound was prepared in a manner analogous to Example 8,using 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 42) and 4-(trifluoromethyl)benzyl bromide. MS (ESI): masscalcd. for C₂₁H₁₃F₆N₃, 421.1; m/z found, 422.3 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.99 (d, J=2.08 Hz, 1H), 8.77 (dd, J=1.97, 1.04 Hz, 1H), 8.45(d, J=0.92 Hz, 1H), 8.08-8.28 (m, 2H), 7.76-7.92 (m, 2H), 7.71 (d,J=8.32 Hz, 2H), 7.47 (d, J=8.09 Hz, 2H), 5.91 (s, 2H).

Example 26:3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]benzonitrile

The title compound was made in an analogous manner to Example 8 using3-(chloromethyl)benzonitrile instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₂₁H₁₃F₃N₄, 378.1; m/z found, 379.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ8.91 (d, J=1.9 Hz, 1H), 8.73-8.64 (m, 1H), 8.42 (s, 1H), 8.15-8.02 (m,2H), 7.83-7.72 (m, 2H), 7.63-7.50 (m, 3H), 7.30 (t, J=54.1 Hz, 1H), 5.83(s, 2H).

Example 27:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(3,5-difluorophenyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using3-(chloromethyl)-3,5-difluorobenzene instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₂₀H₁₂F₅N₃, 389.1; m/z found, 390.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ8.91 (d, J=1.9 Hz, 1H), 8.71-8.60 (m, 1H), 8.43 (s, 1H), 8.13-8.02 (m,2H), 7.64-7.53 (m, 1H), 7.30 (t, J=54.1 Hz, 1H), 7.22-7.11 (m, 1H),7.06-6.91 (m, 2H), 5.79 (s, 2H).

Example 28:3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-fluoro-benzonitrile

The title compound was made in an analogous manner to Example 8 using3-(chloromethyl)-5-fluorobenzonitrile instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₂₁H₁₂F₄N₄, 396.1; m/z found, 397.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.91 (d, J=1.9 Hz, 1H), 8.68-8.65 (m, 1H), 8.44 (s, 1H), 8.12-8.05 (m,2H), 7.82-7.77 (m, 1H), 7.66-7.62 (m, 1H), 7.61-7.55 (m, 1H), 7.54-7.48(m, 1H), 7.30 (t, J=54.1 Hz, 1H), 5.83 (s, 2H).

Example 29:3-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]benzonitrile

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 3-(chloromethyl)benzonitrile. MS (ESI): masscalcd. for C₂₁H₁₃F₃N₄O, 394.1; m/z found, 395.3 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 8.91 (d, J=1.9 Hz, 1H), 8.68-8.60 (m, 1H), 8.42 (s, 1H),7.91-7.82 (m, 1H), 7.83-7.71 (m, 3H), 7.68-7.47 (m, 3H), 7.37 (t, J=73.2Hz, 1H), 5.82 (s, 2H).

Example 30:6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(3,5-difluorophenyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 1-(chloromethyl)-3,5-difluorobenzene. MS (ESI):mass calcd. for C₂₀H₁₂F₅N₃O, 405.1; m/z found, 406.2 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 8.91 (d, J=1.9 Hz, 1H), 8.67-8.59 (m, 1H), 8.43 (s, 1H),7.90-7.82 (m, 1H), 7.82-7.74 (m, 1H), 7.57 (dd, J=8.7, 1.8 Hz, 1H), 7.38(t, J=73.5 Hz, 1H), 7.23-7.10 (m, 1H), 7.03-6.93 (m, 2H), 5.78 (s, 2H).

Example 31:3-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-fluoro-benzonitrile

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 3-(chloromethyl)-5-fluorobenzonitrile. MS (ESI):mass calcd. for C₂₁H₁₂F₄N₄O, 412.3; m/z found, 413.2 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 8.92 (d, J=1.9 Hz, 1H), 8.68-8.61 (m, 1H), 8.44 (s, 1H),7.91-7.83 (m, 1H), 7.85-7.74 (m, 2H), 7.68-7.58 (m, 2H), 7.56-7.46 (m,1H), 7.38 (t, J=73.2 Hz, 1H), 5.82 (s, 2H).

Example 32:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-methyl-2-thienyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using2-(chloromethyl)-5-methylthiophene instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₉H₁₄F₃N₃S, 373.1; m/z found, 374.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ8.88 (d, J=1.9 Hz, 1H), 8.70-8.61 (m, 1H), 8.43-8.31 (m, 1H), 8.16-8.00(m, 2H), 7.64-7.54 (m, 1H), 7.30 (t, J=54.1 Hz, 1H), 7.01 (d, J=3.4 Hz,1H), 6.67-6.58 (m, 1H), 5.86 (s, 2H), 2.33 (s, 3H).

Example 33:6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((5-fluorothiophen-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using2-(chloromethyl)-5-fluorothiophene instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₈H₁₁F₄N₃S, 377.1; m/z found, 378.1 [M+H]⁺.

Example 34:5-((6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)thiophene-2-carbonitrile

The title compound was made in an analogous manner to Example 8 using5-(chloromethyl)thiophene-2-carbonitrile instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₉H₁₁F₃N₄S, 384.1; m/z found, 385.1 [M+H]⁺.

Example 35:6-[3-(1,1-Difluoroethyl)phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 11using 6-(3-(1,1-difluoroethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 29) instead of6-[3-(difluoromethoxy)-4-fluoro-phenyl]-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) in Step A. MS (ESI): mass calcd. for C₁₈H₁₅F₂N₅,339.3; m/z found, 340.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.72 (br s,1H), 8.89 (d, J=1.9 Hz, 1H), 8.54-8.48 (m, 1H), 8.32 (s, 1H), 8.00-7.90(m, 2H), 7.71-7.55 (m, 3H), 6.17-6.09 (m, 1H), 5.73 (s, 2H), 2.07 (t,J=18.9 Hz, 3H).

Example 36:1-[(1-Methylimidazol-4-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 1,using 4-(chloromethyl)-1-methyl-1H-imidazole instead of2-(chloromethyl)pyrimidine hydrochloride. MS (ESI): mass calcd. forC₁₈H₁₄F₃N₅, 357.1; m/z found, 358.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.79 (d, J=1.9 Hz, 1H), 8.28 (d, J=1.0 Hz, 1H), 8.14 (dd, J=1.9, 1.0 Hz,1H), 7.90-7.87 (m, 1H), 7.84 (d, J=7.7 Hz, 1H), 7.71-7.61 (m, 2H),7.38-7.34 (m, 1H), 6.83 (s, 1H), 5.61-5.56 (m, 2H), 3.62 (s, 3H).

Example 37:1-[(2,5-Dimethylpyrazol-3-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 1,using 5-(chloromethyl)-1,3-dimethyl-1H-pyrazole instead of2-(chloromethyl)pyrimidine hydrochloride. MS (ESI): mass calcd. forC₁₉H₁₆F₃N₅, 371.1; m/z found, 372.2 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.81-8.78 (m, 1H), 8.29-8.27 (m, 1H), 8.04-8.00 (m, 1H), 7.88-7.81 (m,2H), 7.72-7.60 (m, 2H), 5.92-5.88 (m, 1H), 5.58 (m, 2H), 3.74 (s, 3H),2.23-2.17 (m, 3H), 2.00 (s, 3H).

Example 38:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 11using 6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 25) instead of6-[3-(difluoromethoxy)-4-fluoro-phenyl]-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) in Step A. MS (ESI): mass calcd. for C₁₇H₁₂F₃N₅,343.1; m/z found, 344.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 12.73 (br s,1H), 8.87 (d, J=1.9 Hz, 1H), 8.59-8.50 (m, 1H), 8.33 (s, 1H), 8.11-8.02(m, 2H), 7.68-7.50 (m, 2H), 7.29 (t, J=54.1 Hz, 1H), 6.19-6.11 (m, 1H),5.72 (s, 2H).

Example 39:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 8 using3-(chloromethyl)-1-methyl-1H-pyrazole hydrochloride instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₈H₁₄F₃N₅, 357.1; m/z found, 358.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.78 (d, J=1.9 Hz, 1H), 8.36 (dd, J=2.0, 1.0 Hz, 1H), 8.23 (d, J=1.0 Hz,1H), 8.03-7.89 (m, 2H), 7.49 (d, J=2.3 Hz, 1H), 7.41 (dd, J=9.9, 8.7 Hz,1H), 7.08 (t, J=54.6 Hz, 1H), 6.20 (d, J=2.3 Hz, 1H), 5.67 (s, 2H), 3.84(s, 3H).

Example 40:6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 11using Intermediate 28:6-(3-(1,1-Difluoroethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine. MS(ESI): mass calcd. for C₁₈H₁₄F₃N₅, 357.1; m/z found, 358.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 12.73 (s, 1H), 8.93-8.82 (m, 1H), 8.55-8.48 (m,1H), 8.32 (s, 1H), 8.06-7.89 (m, 2H), 7.69-7.58 (m, 1H), 7.59-7.50 (m,1H), 6.17-6.08 (m, 1H), 5.72 (s, 2H), 2.10 (t, J=19.2 Hz, 3H).

Example 41:6-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 11using 6-(4-chloro-3-(difluoromethoxy)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 27) instead of6-[3-(difluoromethoxy)-4-fluoro-phenyl]-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) in Step A. MS (ESI): mass calcd. for C₁₇H₁₂ClF₂N₅O,375.1; m/z found, 376.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 12.73 (br s,1H), 8.89 (d, J=1.9 Hz, 1H), 8.60-8.50 (m, 1H), 8.34 (s, 1H), 7.86-7.71(m, 3H), 7.66-7.54 (m, 1H), 7.45 (t, J=73.2 Hz, 1H), 6.19-6.09 (m, 1H),5.72 (s, 2H).

Example 42:5-[[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-isoxazole

The title compound was prepared in a manner analogous to Example 1,using 6-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate 43)and 5-(chloromethyl)-3-methylisoxazole. MS (ESI): mass calcd. forC₁₇H₁₃FN₄O, 308.1; m/z found, 309.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.81 (d, J=1.9 Hz, 1H), 8.31-8.29 (m, 1H), 7.92-7.89 (m, 1H), 7.64-7.58(m, 2H), 7.25-7.16 (m, 2H), 5.98 (s, 1H), 5.70-5.67 (m, 2H), 2.25 (s,3H).

Example 43:3-[[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-isoxazole

The title compound was prepared in a manner analogous to Example 1,using 6-(4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate 43)and 3-(chloromethyl)-5-methylisoxazole. MS (ESI): mass calcd. forC₁₇H₁₃FN₄O, 308.1; m/z found, 309.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.81 (d, J=1.9 Hz, 1H), 8.33 (d, J=1.0 Hz, 1H), 7.94 (dd, J=1.9, 1.0 Hz,1H), 7.86-7.84 (m, 1H), 7.82-7.79 (m, 1H), 7.72-7.60 (m, 2H), 6.77-7.76(m, 1H), 5.72 (s, 2H), 2.49 (d, J=1.0 Hz, 3H).

Example 44:3-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]isoxazole

The title compound was prepared in a manner analogous to Example 1,using 3-(chloromethyl)isoxazole instead of 2-(chloromethyl)pyrimidinehydrochloride. MS (ESI): mass calcd. for C₁₇H₁₁F₃N₄O, 344.1; m/z found,345.1 [M+H]⁺. 1H NMR (500 MHz, CDCl₃) δ 8.84-8.82 (m, 1H), 8.37-8.32 (m,2H), 7.97-7.95 (m, 1H), 7.88-7.85 (m, 1H), 7.83-7.79 (m, 1H), 7.72-7.69(m, 1H), 7.67-7.62 (m, 1H), 6.32-6.29 (m, 1H), 5.76 (s, 2H).

Example 45:3-[[6-[3-(1,1-Difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-isoxazole

The title compound was made in an analogous manner to Example 11, StepA, using 6-(3-(1,1-difluoroethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 29) instead of6-[3-(difluoromethoxy)-4-fluoro-phenyl]-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 3-(chloromethyl)-5-methylisoxazole instead of4-(chloromethyl)-1-tetrahydropyran-2-yl-pyrazole (Intermediate 1). MS(ESI): mass calcd. for C₁₉H₁₆F₂N₄O, 354.1; m/z found, 355.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 8.94 (d, J=1.9 Hz, 1H), 8.67-8.57 (m, 1H),8.44-8.36 (m, 1H), 8.03-7.92 (m, 2H), 7.73-7.60 (m, 2H), 6.07 (s, 1H),5.84 (s, 2H), 2.32 (s, 3H), 2.07 (t, J=18.9 Hz, 3H).

Example 46:4-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazole

The title compound was prepared in a manner analogous to Example 1,using 4-(chloromethyl)oxazole instead of 2-(chloromethyl)pyrimidinehydrochloride. MS (ESI): mass calcd. for C₁₇H₁₁F₃N₄O, 344.1; m/z found,345.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ 8.84-8.81 (m, 1H), 8.32-8.29 (m,1H), 8.09-8.12 (m, 1H), 7.92-7.83 (m, 3H), 7.73-7.63 (m, 3H), 5.62-5.58(m, 2H).

Example 47:5-Methyl-3-[[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]isoxazole

The title compound was prepared in a manner analogous to Example 8,using 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 42) and 3-(chloromethyl)-5-methylisoxazole. MS (ESI): masscalcd. for C₁₈H₁₃F₃N₄O, 358.1; m/z found, 359.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 8.83 (d, J=2.02 Hz, 1H), 8.33 (d, J=0.87 Hz, 1H), 7.97 (dd,J=1.88, 1.01 Hz, 1H), 7.87 (s, 1H), 7.82 (d, J=7.80 Hz, 1H), 7.75-7.69(m, 1H), 7.68-7.57 (m, 1H), 5.91 (s, 1H), 5.68 (s, 2H), 2.37 (d, J=0.87Hz, 3H).

Example 48:5-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-2-methyloxazole

The title compound was prepared in a manner analogous to Example 9 using5-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-2-methyloxazole(Intermediate 23) and (4-fluoro-3-methylphenyl)boronic acid. MS (ESI):mass calcd. for C₁₈H₁₅FN₄O, 322.1; m/z found, 323.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.79 (d, J=1.8 Hz, 1H), 8.43-8.33 (m, 1H), 8.23 (d, J=1.0Hz, 1H), 7.70-7.61 (m, 1H), 7.61-7.55 (m, 1H), 7.24-7.15 (m, 1H), 7.10(s, 1H), 5.76 (s, 2H), 2.44-2.31 (m, 6H).

Example 49:2-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyloxazole

The title compound was prepared in a manner analogous to Example 9 using5-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-2-methyloxazole(Intermediate 23) and (4-fluoro-3-methylphenyl)boronic acid. MS (ESI):mass calcd. for C₁₈H₁₅FN₄O, 322.1; m/z found, 323.1 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.81 (d, J=1.9 Hz, 1H), 8.35 (dd, J=1.9, 1.0 Hz, 1H), 8.25(d, J=1.0 Hz, 1H), 7.70-7.63 (m, 1H), 7.63-7.55 (m, 1H), 7.24-7.12 (m,1H), 6.76 (d, J=1.2 Hz, 1H), 5.81 (s, 2H), 2.38 (d, J=2.0 Hz, 3H), 2.27(d, J=1.2 Hz, 3H).

Example 50:5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]isoxazole

The title compound was prepared in a manner analogous to Example 8 using5-(chloromethyl)isoxazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₇H₁₁F₃N₄O, 344.1; m/z found, 345.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.83 (d, J=1.9 Hz, 1H), 8.45 (dd, J=1.9, 1.0 Hz, 1H), 8.32 (d, J=1.6 Hz,1H), 8.29 (d, J=1.0 Hz, 1H), 8.03-7.91 (m, 2H), 7.46-7.34 (m, 1H), 7.07(t, J=54.6 Hz, 1H), 6.39-6.33 (m, 1H), 5.95 (s, 2H).

Example 51:3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]isoxazole

The title compound was prepared in a manner analogous to Example 8 using3-(chloromethyl)isoxazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₇H₁₁F₃N₄O, 344.1; m/z found, 345.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.82 (d, J=1.9 Hz, 1H), 8.61 (d, J=1.7 Hz, 1H), 8.40 (dd, J=1.9, 1.0 Hz,1H), 8.29 (d, J=1.0 Hz, 1H), 8.02-7.91 (m, 2H), 7.41 (ddt, J=9.8, 8.7,1.1 Hz, 1H), 7.07 (t, J=54.6 Hz, 1H), 6.41 (d, J=1.7 Hz, 1H), 5.87 (s,2H).

Example 52:5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-isoxazole

The title compound was prepared in a manner analogous to Example 8 using5-(chloromethyl)-3-methylisoxazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₈H₁₃F₃N₄O, 358.1; m/z found, 359.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.84 (d, J=1.9 Hz, 1H), 8.45 (dd, J=1.9, 1.0 Hz, 1H), 8.30 (d, J=1.0 Hz,1H), 8.07-7.90 (m, 2H), 7.42 (dd, J=10.1, 8.6 Hz, 1H), 7.08 (t, J=54.6Hz, 1H), 6.21 (s, 1H), 5.88 (s, 2H), 2.22 (s, 3H).

Example 53:3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-isoxazole

The title compound was made in an analogous manner to Example 11, StepA, using6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 25) instead of6-[3-(difluoromethoxy)-4-fluoro-phenyl]-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 3-(chloromethyl)-5-methylisoxazole instead of4-(chloromethyl)-1-tetrahydropyran-2-yl-pyrazole (Intermediate 1). MS(ESI): mass calcd. for C₁₈H₁₃F₃N₄O, 358.1; m/z found, 359.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 8.92 (d, J=1.9 Hz, 1H), 8.67-8.59 (m, 1H),8.44-8.37 (m, 1H), 8.14-8.04 (m, 2H), 7.64-7.53 (m, 1H), 7.30 (t, J=54.1Hz, 1H), 6.07 (s, 1H), 5.82 (s, 2H), 2.32 (s, 3H).

Example 54:5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-2-methyloxazole

The title compound was prepared in a manner analogous to Example 8 using5-(chloromethyl)-2-methyloxazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₈H₁₃F₃N₄O, 358.1; m/z found, 359.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.83 (d, J=1.9 Hz, 1H), 8.48 (dd, J=1.9, 1.0 Hz, 1H), 8.27 (d, J=1.0 Hz,1H), 8.07-7.90 (m, 2H), 7.44 (dd, J=10.0, 8.7 Hz, 1H), 7.25-6.93 (m,2H), 5.79 (s, 2H), 2.37 (s, 3H).

Example 55:4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-2-methyloxazole

The title compound was prepared in a manner analogous to Example 8 using4-(chloromethyl)-2-methyloxazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₈H₁₃F₃N₄O, 358.1; m/z found, 359.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.81 (d, J=1.9 Hz, 1H), 8.47 (dd, J=1.9, 1.0 Hz, 1H), 8.24 (d, J=1.0 Hz,1H), 8.07-7.93 (m, 2H), 7.89-7.80 (m, 1H), 7.42 (t, J=9.3 Hz, 1H), 7.09(t, J=54.6 Hz, 1H), 5.60 (d, J=0.9 Hz, 2H), 2.37 (s, 3H).

Example 56:3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-4-methyl-isoxazole

The title compound was prepared in a manner analogous to Example 8 using4-(chloromethyl)-3-methylisoxazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₈H₁₃F₃N₄O, 358.1; m/z found, 359.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.81 (d, J=1.9 Hz, 1H), 8.40-8.35 (m, 2H), 8.27 (d, J=1.0 Hz, 1H),8.03-7.87 (m, 2H), 7.48-7.36 (m, 1H), 7.27-6.88 (m, 1H), 5.83 (d, J=0.6Hz, 2H), 1.92 (d, J=1.1 Hz, 3H).

Example 57:4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3,5-dimethyl-isoxazole

The title compound was prepared in a manner analogous to Example 8 using4-(chloromethyl)-3,5-dimethylisoxazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₉H₁₅F₃N₄O, 372.1; m/z found, 373.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.80 (d, J=1.9 Hz, 1H), 8.41 (dd, J=1.9, 1.0 Hz, 1H), 8.24 (d, J=1.0 Hz,1H), 8.06-7.90 (m, 2H), 7.48-7.37 (m, 1H), 7.08 (t, J=54.6 Hz, 1H), 5.52(s, 2H), 2.45 (s, 3H), 2.15 (s, 3H).

Example 58:3-[[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-isoxazole

The title compound was made in a manner analogous to Example 11, Step A,using6-(3-(1,1-difluoroethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 28) instead of6-[3-(difluoromethoxy)-4-fluoro-phenyl]-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 3-(chloromethyl)-5-methylisoxazole instead of4-(chloromethyl)-1-tetrahydropyran-2-yl-pyrazole (Intermediate 1). MS(ESI): mass calcd. for C₁₉H₁₅F₃N₄O, 372.1; m/z found, 373.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 8.92 (d, J=1.9 Hz, 1H), 8.65-8.57 (m, 1H),8.44-8.36 (m, 1H), 8.08-8.00 (m, 1H), 7.97 (dd, J=7.2, 2.3 Hz, 1H), 7.56(dd, J=11.0, 8.6 Hz, 1H), 6.10-6.02 (m, 1H), 5.83 (s, 2H), 2.32 (s, 3H),2.10 (t, J=19.1 Hz, 3H).

Example 59:3-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-isoxazole

The title compound was made in an analogous manner to Example 11, StepA, using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 3-(chloromethyl)-5-methylisoxazole instead of4-(chloromethyl)-1-tetrahydropyran-2-yl-pyrazole (Intermediate 1). MS(ESI): mass calcd. for C₁₈H₁₃F₃N₄O₂, 374.1; m/z found, 375.2 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.91 (d, J=1.9 Hz, 1H), 8.59-8.55 (m, 1H),8.41-8.37 (m, 1H), 7.85 (dd, J=7.6, 2.3 Hz, 1H), 7.80-7.76 (m, 1H), 7.60(dd, J=10.5, 8.6 Hz, 1H), 7.37 (t, J=73.2 Hz, 1H), 6.07 (s, 1H), 5.81(s, 2H), 2.33 (s, 3H).

Example 60:5-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-2-methyloxazole

The title compound was prepared in a manner analogous to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 5-(chloromethyl)-2-methyloxazole. MS (ESI): masscalcd. for C₁₈H₁₃F₃N₄O₂, 374.1; m/z found, 375.1 [M+H]⁺. ¹H NMR (600MHz, CD₃OD) δ 8.82 (s, 1H), 8.45 (dd, J=1.9, 1.0 Hz, 1H), 8.26 (d, J=1.0Hz, 1H), 7.78-7.62 (m, 2H), 7.45 (dd, J=10.3, 8.6 Hz, 1H), 7.17-6.81 (m,2H), 5.78 (d, J=0.8 Hz, 2H), 2.37 (s, 3H).

Example 61:2-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyloxazole

The title compound was prepared in a manner analogous to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI):mass calcd. for C₁₈H₁₃F₃N₄O₂, 374.1; m/z found, 375.1 [M+H]⁺. ¹H NMR(600 MHz, CD₃OD) δ 8.83 (d, J=1.9 Hz, 1H), 8.42 (dd, J=1.8, 1.0 Hz, 1H),8.28 (d, J=1.1 Hz, 1H), 7.78-7.64 (m, 2H), 7.44 (dd, J=10.3, 8.5 Hz,1H), 6.99 (t, J=73.3 Hz, 1H), 6.76 (d, J=1.6 Hz, 1H), 5.83 (s, 2H), 2.27(d, J=1.2 Hz, 3H).

Example 62:3-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-isoxazole

The title compound was made in an analogous manner to Example 11, StepA, using6-(4-chloro-3-(difluoromethoxy)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 27) instead of6-[3-(difluoromethoxy)-4-fluoro-phenyl]-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 3-(chloromethyl)-5-methylisoxazole instead of4-(chloromethyl)-1-tetrahydropyran-2-yl-pyrazole (Intermediate 1). MS(ESI): mass calcd. for C₁₈H₁₃ClF₂N₄O₂, 390.1; m/z found, 391.2 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.94 (d, J=1.9 Hz, 1H), 8.63-8.60 (m, 1H),8.43-8.39 (m, 1H), 7.85-7.82 (m, 1H), 7.80-7.75 (m, 2H), 7.44 (t, J=73.2Hz, 1H), 6.09-6.05 (m, 1H), 5.82 (s, 2H), 2.33 (s, 3H).

Example 63:5-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-2-methyloxazole

The title compound was prepared in a manner analogous to Example 9 using5-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-2-methyloxazole(Intermediate 22) and (2,4-difluoro-3-methylphenyl)boronic acid. MS(ESI): mass calcd. for C₁₈H₁₄F₂N₄O, 340.1; m/z found, 341.1 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.72-8.64 (m, 1H), 8.34 (d, J=1.5 Hz, 1H), 8.26(d, J=1.0 Hz, 1H), 7.56-7.41 (m, 1H), 7.16-7.06 (m, 2H), 5.76 (d, J=0.9Hz, 2H), 2.37 (s, 3H), 2.30 (t, J=2.0 Hz, 3H).

Example 64:5-Methyl-3-[[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]isothiazole

The title compound was prepared in a manner analogous to Example 1,using 3-(chloromethyl)-5-methylisothiazole instead of2-(chloromethyl)pyrimidine hydrochloride. MS (ESI): mass calcd. forC₁₈H₁₃F₃N₄S, 374.1; m/z found, 375.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.81 (d, J=1.9 Hz, 1H), 8.33 (d, J=1.0 Hz, 1H), 7.94 (dd, J=1.9, 1.0 Hz,1H), 7.86-7.84 (m, 1H), 7.82-7.79 (m, 1H), 7.72-7.60 (m, 2H), 6.77-7.76(m, 1H), 5.72 (s, 2H), 2.49 (d, J=1.0 Hz, 3H).

Example 65:2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-thiazole

The title compound was prepared in a manner analogous to Example 8 using2-(chloromethyl)-5-methylthiazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₈H₁₃F₃N₄S, 374.1; m/z found, 375.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.83 (d, J=1.9 Hz, 1H), 8.43 (dd, J=1.9, 1.0 Hz, 1H), 8.30 (d, J=1.0 Hz,1H), 8.07-7.88 (m, 2H), 7.49-7.32 (m, 2H), 7.07 (t, J=54.6 Hz, 1H), 5.97(s, 2H), 2.41 (d, J=1.2 Hz, 3H).

Example 66:2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-4-methyl-thiazole

The title compound was prepared in a manner analogous to Example 8 using4-(chloromethyl)-2-methylthiazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₈H₁₃F₃N₄S, 374.1; m/z found, 375.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.83 (d, J=1.9 Hz, 1H), 8.46 (dd, J=1.9, 1.0 Hz, 1H), 8.30 (d, J=1.0 Hz,1H), 8.06-7.88 (m, 2H), 7.48-7.33 (m, 1H), 7.23-6.90 (m, 2H), 6.00 (s,2H), 2.39 (d, J=1.0 Hz, 3H).

Example 67:4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-2-methyl-thiazole

The title compound was prepared in a manner analogous to Example 8 using4-(chloromethyl)-2-methylthiazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₈H₁₃F₃N₄S, 374.1; m/z found, 375.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.81 (d, J=1.9 Hz, 1H), 8.47-8.40 (m, 1H), 8.26 (d, J=1.0 Hz, 1H),8.05-7.91 (m, 2H), 7.47-7.36 (m, 1H), 7.30-7.25 (m, 1H), 7.23-6.94 (m,1H), 5.76 (d, J=0.8 Hz, 2H), 2.64 (s, 3H).

Example 68:2-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-thiazole

The title compound was prepared in a manner analogous to Example 8 using6-(4-fluoro-3-methylphenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate 34)and 2-(chloromethyl)-5-methyl-1,3-thiazole. MS (ESI): mass calcd. forC₁₈H₁₅FN₄S, 338.1; m/z found, 339.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.79 (d, J=1.9 Hz, 1H), 8.35 (dd, J=1.8, 1.0 Hz, 1H), 8.27 (d, J=1.0 Hz,1H), 7.64 (ddd, J=7.2, 2.4, 1.0 Hz, 1H), 7.60-7.52 (m, 1H), 7.40 (d,J=1.2 Hz, 1H), 7.18 (dd, J=9.6, 8.5 Hz, 1H), 5.96 (s, 2H), 2.40 (d,J=1.2 Hz, 3H), 2.37 (d, J=1.9 Hz, 3H).

Example 69:2-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-thiazole

The title compound was prepared in a manner analogous to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 2-(chloromethyl)-5-methyl-1,3-thiazole. MS (ESI):mass calcd. for C₁₈H₁₃F₃N₄OS, 390.1; m/z found, 391.0 [M+H]⁺. ¹H NMR(500 MHz, CD₃OD) δ 8.81 (d, J=1.9 Hz, 1H), 8.40 (dd, J=2.0, 1.0 Hz, 1H),8.29 (d, J=0.9 Hz, 1H), 7.70 (dd, J=7.4, 2.3 Hz, 1H), 7.66 (ddd, J=8.6,4.3, 2.3 Hz, 1H), 7.49-7.34 (m, 2H), 6.97 (t, J=73.3 Hz, 1H), 5.97 (s,2H), 2.41 (d, J=1.2 Hz, 3H).

Example 70:2-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-thiazole

The title compound was prepared in a manner analogous to Example 8 using6-(2,4-difluoro-3-methylphenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate36) and 2-(chloromethyl)-5-methyl-1,3-thiazole. MS (ESI): mass calcd.for C₁₈H₁₄F₂N₄S, 356.1; m/z found, 357.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD)δ 8.68 (t, J=1.8 Hz, 1H), 8.36-8.19 (m, 2H), 7.46 (td, J=8.7, 6.4 Hz,1H), 7.40 (q, J=1.2 Hz, 1H), 7.10 (td, J=8.7, 1.5 Hz, 1H), 5.96 (s, 2H),2.41 (d, J=1.2 Hz, 3H), 2.29 (t, J=2.0 Hz, 3H).

Example 71:1-[(1-Methyl-1,2,4-triazol-3-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 1,using 3-(chloromethyl)-1-methyl-1H-1,2,4-triazole instead of2-(chloromethyl)pyrimidine hydrochloride. MS (ESI): mass calcd. forC₁₇H₁₃F₃N₆, 358.1; m/z found, 359.1 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.85-8.81 (m, 1H), 8.31-8.28 (m, 1H), 8.12-8.10 (m, 1H), 7.88-7.80 (m,3H), 7.74-7.62 (m, 2H), 5.83-5.81 (m, 2H), 3.98-3.96 (m, 3H).

Example 72:6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(1-methyltriazol-4-yl)methyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 8 usingIntermediate 26,6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine and4-(chloromethyl)-1-methyl-1H-1,3,4-triazole hydrochloride. MS (ESI):mass calcd. for C₁₇H₁₃F₃N₆O, 374.1; m/z found, 375.1 [M+H]⁺.

Example 73:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 8 using3-(chloromethyl)-1-methyl-1H-1,2,4-triazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₇H₁₃F₃N₆, 358.1; m/z found, 359.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.83 (s, 1H), 8.45 (d, J=1.8 Hz, 1H), 8.32 (d, J=38.1 Hz, 2H), 8.05-7.90(m, 2H), 7.42 (dd, J=9.9, 8.7 Hz, 1H), 7.09 (t, J=54.6 Hz, 1H), 5.77 (s,2H), 3.88 (s, 3H).

Example 74:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(4-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using3-(chloromethyl)-4-methyl-4H-1,2,4-triazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₇H₁₃F₃N₆, 358.1; m/z found, 359.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.91 (d, J=1.9 Hz, 1H), 8.61-8.56 (m, 1H), 8.45 (s, 1H), 8.40 (s, 1H),8.11-8.03 (m, 2H), 7.64-7.56 (m, 1H), 7.31 (t, J=54.1 Hz, 1H), 6.00 (s,2H), 3.66 (s, 3H).

Example 75:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(4,5-dimethyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using3-(chloromethyl)-4,5-dimethyl-4H-1,2,4-triazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₈H₁₅F₃N₆, 372.1; m/z found, 373.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ8.90 (d, J=1.9 Hz, 1H), 8.61-8.53 (m, 1H), 8.39 (s, 1H), 8.13-8.00 (m,2H), 7.65-7.55 (m, 1H), 7.31 (t, J=54.1 Hz, 1H), 5.95 (s, 2H), 3.54 (s,3H), 2.30 (s, 3H).

Example 76:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-ethyl-4-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using3-(chloromethyl)-5-ethyl-4-methyl-4H-1,2,4-triazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₉H₁₇F₃N₆, 386.2; m/z found, 387.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.90 (d, J=2.0 Hz, 1H), 8.58-8.55 (m, 1H), 8.39 (d, J=1.0 Hz, 1H),8.10-8.03 (m, 2H), 7.63-7.55 (m, 1H), 7.31 (t, J=54.1 Hz, 1H), 5.95 (s,2H), 3.55 (s, 3H), 2.67 (q, J=7.5 Hz, 2H), 1.20 (t, J=7.5 Hz, 3H).

Example 77:2-[[6-(5-Chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole

The title compound was made in an analogous manner to Intermediate 41using2-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole(Intermediate 19) and (5-chlorothiophen-2-yl)boronic acid. MS (ESI):mass calcd. for C₁₄H₁₀ClN₅OS, 331.1; m/z found, 332.1 [M+H]⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 8.92 (d, J=2.0 Hz, 1H), 8.51-8.48 (m, 1H),8.42-8.40 (m, 1H), 7.64 (d, J=4.0 Hz, 1H), 7.28 (d, J=4.0 Hz, 1H), 6.06(s, 2H), 2.45 (s, 3H).

Example 78:2-Methyl-5-[[6-[5-(trifluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-oxadiazole

The title compound was made in an analogous manner to Intermediate 41using2-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole(Intermediate 19) and (5-(trifluoromethyl)thiophen-2-yl)boronic acid. MS(ESI): mass calcd. for C₁₅H₁₀F₃N₅OS, 365.1; m/z found, 366.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 9.03 (d, J=2.0 Hz, 1H), 8.74-8.65 (m, 1H),8.51-8.40 (m, 1H), 7.90-7.79 (m, 2H), 6.09 (s, 2H), 2.45 (s, 3H).

Example 79:2-[[6-[5-(Difluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole

The title compound was made in an analogous manner to Intermediate 41using2-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole(Intermediate 19) and2-(5-(difluoromethyl)thiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Intermediate 12). MS (ESI): mass calcd. for C₁₅H₁₁F₂N₅OS, 347.1; m/zfound, 348.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 9.00 (d, J=1.9 Hz, 1H),8.70-8.57 (m, 1H), 8.49-8.38 (m, 1H), 7.81-7.71 (m, 1H), 7.62-7.56 (m,1H), 7.38 (t, J=55.2 Hz, 1H), 6.09 (s, 2H), 2.45 (s, 3H).

Example 80:5-[[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole

The title compound was prepared in a manner analogous to Intermediate 42using5-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-3-methyl-1,2,4-oxadiazole(Intermediate 55) and (4-fluorophenyl)boronic acid. MS (ESI): masscalcd. for C₁₆H₁₂FN₅O, 309.1; m/z found, 310.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 8.83 (d, J=1.9 Hz, 1H), 8.34 (d, J=1.1 Hz, 1H), 7.89 (dd,J=1.9, 1.0 Hz, 1H), 7.65-7.59 (m, 2H), 7.25-7.19 (m, 2H), 5.83 (s, 2H),2.38 (s, 3H).

Example 81:5-[[6-(3-Methoxyphenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole

The title compound was prepared in a manner analogous to Intermediate 42using5-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-3-methyl-1,2,4-oxadiazole(Intermediate 55) and (3-methoxyphenyl)boronic acid. MS (ESI): masscalcd. for C₁₇H₁₅N₅O₂, 321.1; m/z found, 322.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.98-8.92 (m, 1H), 8.61-8.58 (m, 1H), 8.46-8.42 (m, 1H),7.51-7.43 (m, 1H), 7.43-7.34 (m, 2H), 7.07-7.01 (m, 1H), 6.20 (s, 2H),3.86 (s, 3H), 2.28 (s, 3H).

Example 82:2-[[6-[3-(1,1-Difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole

The title compound was made in an analogous manner to Intermediate 25using2-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole(Intermediate 19) and2-(3-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₈H₁₅F₂N₅O, 355.1; m/z found, 356.2 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.97 (d, J=1.9 Hz, 1H), 8.63 (dd, J=2.0, 1.0Hz, 1H), 8.44 (d, J=0.9 Hz, 1H), 8.01-7.95 (m, 2H), 7.72-7.64 (m, 2H),6.11 (s, 2H), 2.44 (s, 3H), 2.07 (t, J=18.9 Hz, 3H).

Example 83:2-[[6-[3-(1,1-Difluoroethyl)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole

The title compound was made in an analogous manner to Example 8 using6-(3-(1,1-Difluoroethyl)phenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine(Intermediate 33) and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole. MS(ESI): mass calcd. for C₁₈H₁₄F₃N₅O, 373.1; m/z found, 374.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 9.03 (d, J=1.8 Hz, 1H), 8.74-8.65 (m, 1H),8.03-7.94 (m, 2H), 7.75-7.64 (m, 2H), 6.01 (s, 2H), 2.46 (s, 3H), 2.07(t, J=18.9 Hz, 3H).

Example 84:3-Methyl-5-[[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,2,4-oxadiazole

The title compound was prepared in a manner analogous to Example 8,using 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 42) and 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole. MS(ESI): mass calcd. for C₁₇H₁₂F₃N₅O, 359.1; m/z found, 360.6 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 8.87 (d, J=1.73 Hz, 1H), 8.37 (s, 1H), 8.07-7.92(m, 1H), 7.89 (s, 1H), 7.84 (d, J=7.80 Hz, 1H), 7.76-7.69 (m, 1H),7.69-7.59 (m, 1H), 5.86 (s, 2H), 2.38 (s, 3H).

Example 85:2-Methyl-5-[[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-oxadiazole

The title compound was prepared in a manner analogous to Example 8,using 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 42) and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole. MS(ESI): mass calcd. for C₁₇H₁₂F₃N₅O, 359.1; m/z found, 360.3 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 8.87 (d, J=1.73 Hz, 1H), 8.36 (d, J=0.87 Hz, 1H),8.12-7.98 (m, 1H), 7.89 (s, 1H), 7.84 (d, J=7.80 Hz, 1H), 7.77-7.70 (m,1H), 7.69-7.63 (m, 1H), 5.85 (s, 2H), 2.67-2.30 (m, 3H).

Example 86:5-Methyl-3-[[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,2,4-oxadiazole

The title compound was prepared in a manner analogous to Example 8,using 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 42) and 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole. MS(ESI): mass calcd. for C₁₇H₁₂F₃N₅O, 359.1; m/z found, 360.1 [M+H]⁺. ¹HNMR (500 MHz, CDCl₃) δ 8.85 (d, J=1.73 Hz, 1H), 8.36 (d, J=1.16 Hz, 1H),8.02 (dd, J=1.88, 1.01 Hz, 1H), 7.90 (s, 1H), 7.85 (d, J=7.51 Hz, 1H),7.75-7.70 (m, 1H), 7.69-7.63 (m, 1H), 5.75 (s, 2H), 2.56 (s, 3H).

Example 87:5-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,2,4-oxadiazole

The title compound was prepared in a manner analogous to Example 20,using 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 42) and 5-(chloromethyl)-1,2,4-oxadiazole. MS (ESI): masscalcd. for C₁₆H₁₀F₃N₅O, 345.1; m/z found, 346.1 [M+H]⁺. ¹H NMR (500 MHz,CDCl₃) δ 8.88 (d, J=1.73 Hz, 1H), 8.42 (s, 1H), 8.39 (d, J=0.87 Hz, 1H),8.02-7.94 (m, 1H), 7.89 (s, 1H), 7.84 (d, J=7.80 Hz, 1H), 7.77-7.70 (m,1H), 7.69-7.61 (m, 1H), 5.95 (s, 2H).

Example 88:2-Methyl-5-[[6-[2-(trifluoromethyl)-4-pyridyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-oxadiazole

The title compound was made in an analogous manner to Intermediate 25using2-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole(Intermediate 19) and (2-(trifluoromethyl)pyridin-4-yl)boronic acid. MS(ESI): mass calcd. for C₁₆H₁₁F₃N₆O, 360.1; m/z found, 361.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 9.14 (d, J=1.9 Hz, 1H), 9.00-8.85 (m, 2H), 8.51(s, 1H), 8.44-8.35 (m, 1H), 8.30-8.20 (m, 1H), 6.12 (s, 2H), 2.45 (s,3H).

Example 89:2-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole

The title compound was made in an analogous manner to Intermediate 25using2-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole(Intermediate 19) and (4-fluoro-3-methylphenyl)boronic acid. MS (ESI):mass calcd. for C₁₇H₁₄FN₅O, 323.1; m/z found, 324.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.96-8.82 (m, 1H), 8.57-8.50 (m, 1H), 8.45-8.36 (m, 1H),7.82-7.74 (m, 1H), 7.71-7.64 (m, 1H), 7.37-7.29 (m, 1H), 6.08 (s, 2H),2.44 (s, 3H), 2.35 (s, 3H).

Example 90:2-[[3-Fluoro-6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole

The title compound was made in an analogous manner to Intermediate 25using2-((6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole(Intermediate 20) and (4-fluoro-3-methylphenyl)boronic acid. MS (ESI):mass calcd. for C₁₇H₁₃F₂N₅O, 341.1; m/z found, 342.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.95 (d, J=1.9 Hz, 1H), 8.61-8.56 (m, 1H), 7.80 (dd,J=7.3, 2.4 Hz, 1H), 7.73-7.68 (m, 1H), 7.38-7.31 (m, 1H), 6.01-5.92 (m,2H), 2.45 (s, 3H), 2.35 (d, J=1.9 Hz, 3H).

Example 91:2-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-(trifluoromethyl)-1,3,4-oxadiazole

The title compound was prepared in a manner analogous to Example 8 using6-(4-fluoro-3-methylphenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate 34)and 2-(chloromethyl)-5-(trifluoromethyl)-1,3,4-oxadiazole. MS (ESI):mass calcd. for C₁₇H₁₁F₄N₅O, 377.1; m/z found, 378.0 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.84 (d, J=1.9 Hz, 1H), 8.41 (dd, J=1.9, 1.0 Hz, 1H), 8.31(d, J=1.0 Hz, 1H), 7.66 (ddd, J=7.3, 2.5, 1.0 Hz, 1H), 7.59 (ddd, J=7.8,4.8, 2.5 Hz, 1H), 7.20 (dd, J=9.5, 8.5 Hz, 1H), 6.17 (s, 2H), 2.37 (d,J=1.9 Hz, 3H).

Example 92:2-[[6-(3-Chloro-4-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole

The title compound was made in an analogous manner to Intermediate 25using2-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole(Intermediate 19) and (3-chloro-4-fluorophenyl)boronic acid. MS (ESI):mass calcd. for C₁₆H₁₁ClFN₅O, 343.1; m/z found, 344.1 [M+H]⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 8.99-8.91 (m, 1H), 8.67-8.61 (m, 1H), 8.47-8.40 (m,1H), 8.15-8.06 (m, 1H), 7.92-7.84 (m, 1H), 7.62 (t, J=9.0 Hz, 1H), 6.08(s, 2H), 2.44 (s, 3H).

Example 93:2-[[6-(3-Chloro-4-fluoro-phenyl)-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole

The title compound was made in an analogous manner to Intermediate 25using2-((6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole(Intermediate 20) and (3-chloro-4-fluorophenyl)boronic acid. MS (ESI):mass calcd. for C₁₆H₁₀ClF₂N₅O, 361.1; m/z found, 362.1 [M+H]⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 9.00 (d, J=1.9 Hz, 1H), 8.71-8.67 (m, 1H), 8.13(dd, J=7.1, 2.4 Hz, 1H), 7.94-7.86 (m, 1H), 7.64 (t, J=8.9 Hz, 1H), 5.97(s, 2H), 2.46 (s, 3H).

Example 94:2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-oxadiazole

The title compound was prepared in a manner analogous to Example 8 using2-(chloromethyl)-1,3,4-oxadiazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₆H₁₀F₃N₅O, 345.1; m/z found, 346.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.92 (s, 1H), 8.87 (d, J=1.9 Hz, 1H), 8.50 (dd, J=1.9, 1.0 Hz, 1H), 8.32(d, J=1.0 Hz, 1H), 8.02 (d, J=6.1 Hz, 1H), 7.98 (dd, J=8.8, 4.5 Hz, 1H),7.43 (t, J=9.3 Hz, 1H), 7.08 (t, J=54.6 Hz, 1H), 6.11 (s, 2H).

Example 95:5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole

The title compound was made in an analogous manner to Example 8 using5-(chloromethyl)-3-methyl-1,2,4-oxadiazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₇H₁₂F₃N₅O, 359.1; m/z found, 360.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ8.96 (d, J=1.9 Hz, 1H), 8.69-8.63 (m, 1H), 8.50-8.43 (m, 1H), 8.13-8.04(m, 2H), 7.64-7.53 (m, 1H), 7.30 (t, J=54.1 Hz, 1H), 6.21 (s, 2H), 2.28(s, 3H).

Example 96:2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethyl)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine(Intermediate 30) and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole. MS(ESI): mass calcd. for C₁₇H₁₁F₄N₅O, 377.1; m/z found, 378.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 9.00 (d, J=1.8 Hz, 1H), 8.75-8.65 (m, 1H),8.17-8.04 (m, 2H), 7.69-7.54 (m, 1H), 7.32 (t, J=54.1 Hz, 1H), 5.99 (s,2H), 2.46 (s, 3H).

Example 97:3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,2,4-oxadiazole

The title compound was made in an analogous manner to Example 8 using3-(chloromethyl)-5-methyl-1,2,4-oxadiazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₇H₁₂F₃N₅O, 359.1; m/z found, 360.3 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.93 (d, J=2.1 Hz, 1H), 8.66-8.60 (m, 1H), 8.43-8.37 (m, 1H), 8.12-8.05(m, 2H), 7.65-7.53 (m, 1H), 7.30 (t, J=54.2 Hz, 1H), 5.95 (s, 2H), 2.52(s, 3H).

Example 98:3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-4-methyl-1,2,5-oxadiazole

The title compound was prepared in a manner analogous to Example 8 using3-(chloromethyl)-4-methyl-1,2,5-oxadiazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₇H₁₂F₃N₅O, 359.1; m/z found, 360.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.84 (d, J=1.9 Hz, 1H), 8.44 (dd, J=1.9, 1.0 Hz, 1H), 8.29 (d, J=1.0 Hz,1H), 8.05-7.88 (m, 2H), 7.42 (ddt, J=9.8, 8.6, 1.1 Hz, 1H), 7.08 (t,J=54.6 Hz, 1H), 5.97 (s, 2H), 2.29 (s, 3H).

Example 99:2-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-oxadiazole

The title compound was prepared in a manner analogous to Example 8 using2-(chloromethyl)-5-cyclopropyl-1,3,4-oxadiazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₉H₁₄F₃N₅O, 385.1; m/z found, 386.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.84 (s, 1H), 8.53-8.37 (m, 1H), 8.34-8.22 (m, 1H), 8.07-7.86 (m, 2H),7.41 (t, J=9.2 Hz, 1H), 7.08 (t, J=54.6 Hz, 1H), 5.98 (s, 2H), 2.24-2.07(m, 1H), 1.21-1.09 (m, 2H), 1.09-0.95 (m, 2H).

Example 100:2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-isopropyl-1,3,4-oxadiazole

The title compound was prepared in a manner analogous to Example 8 using2-(chloromethyl)-5-isopropyl-1,3,4-oxadiazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₉H₁₆F₃N₅O, 387.1; m/z found, 388.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.87 (d, J=1.9 Hz, 1H), 8.50 (dd, J=1.8, 1.0 Hz, 1H), 8.32 (d, J=1.0 Hz,1H), 8.06-7.92 (m, 2H), 7.43 (dd, J=9.9, 8.7 Hz, 1H), 7.09 (t, J=54.6Hz, 1H), 6.04 (s, 2H), 3.17 (dt, J=14.0, 7.0 Hz, 1H), 1.32 (d, J=7.0 Hz,6H).

Example 101:5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-N,N-dimethyl-1,3,4-oxadiazol-2-amine

The title compound was prepared in a manner analogous to Example 8 using5-(chloromethyl)-N,N-dimethyl-1,3,4-oxadiazol-2-amine instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₈H₁₅F₃N₆O, 388.1; m/z found, 389.1 [M+H]⁺. ¹H NMR (400 MHz, CD₃OD) δ8.85 (d, J=1.9 Hz, 1H), 8.59-8.41 (m, 1H), 8.30 (d, J=1.0 Hz, 1H),8.07-7.89 (m, 2H), 7.52-7.35 (m, 1H), 7.26-6.92 (m, 1H), 5.86 (s, 2H),3.00 (s, 6H).

Example 102:2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-(trifluoromethyl)-1,3,4-oxadiazole

The title compound was prepared in a manner analogous to Example 8 using2-(chloromethyl)-5-(trifluoromethyl)-1,3,4-oxadiazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₇H₉F₆N₅O, 413.1; m/z found, 414.1 [M+H]⁺. ¹H NMR (600 MHz, CD₃OD) δ8.88 (s, 1H), 8.51 (dt, J=1.8, 0.9 Hz, 1H), 8.35 (d, J=1.0 Hz, 1H), 8.02(d, J=6.3 Hz, 1H), 7.98 (dt, J=7.7, 3.3 Hz, 1H), 7.43 (dd, J=10.0, 8.7Hz, 1H), 7.09 (t, J=54.6 Hz, 1H), 6.19 (s, 2H).

Example 103:2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-phenyl-1,3,4-oxadiazole

The title compound was prepared in a manner analogous to Example 8 using2-(chloromethyl)-5-phenyl-1,3,4-oxadiazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₂₂H₁₄F₃N₅O, 421.1; m/z found, 422.1 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.88 (d, J=1.9 Hz, 1H), 8.56 (dd, J=1.9, 1.0 Hz, 1H), 8.35 (d, J=1.0 Hz,1H), 8.04 (d, J=6.1 Hz, 1H), 8.02-7.95 (m, 3H), 7.64-7.56 (m, 1H),7.56-7.50 (m, 2H), 7.43 (dd, J=10.1, 8.6 Hz, 1H), 7.09 (t, J=54.6 Hz,1H), 6.15 (s, 2H).

Example 104:2-[[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole

The title compound was made in an analogous manner to Intermediate 25using2-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole(Intermediate 19) and2-(3-(1,1-difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₈H₁₄F₃N₅O, 373.1; m/z found, 374.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.94 (d, J=1.9 Hz, 1H), 8.62 (dd, J=2.0, 1.0Hz, 1H), 8.44 (d, J=1.0 Hz, 1H), 8.05-8.00 (m, 1H), 7.97 (dd, J=7.2, 2.4Hz, 1H), 7.57 (dd, J=11.0, 8.5 Hz, 1H), 6.10 (s, 2H), 2.44 (s, 3H), 2.10(t, J=19.3 Hz, 3H).

Example 105:2-[[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole

The title compound was made in an analogous manner to Intermediate 25using2-((6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole(Intermediate 20) and2-(3-(1,1-difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₈H₁₃F₄N₅O, 391.1; m/z found, 392.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 9.00 (d, J=1.8 Hz, 1H), 8.70-8.65 (m, 1H),8.08-8.02 (m, 1H), 8.02-7.97 (m, 1H), 7.59 (dd, J=11.0, 8.6 Hz, 1H),5.99 (s, 2H), 2.45 (s, 3H), 2.10 (t, J=19.1 Hz, 3H).

Example 106:2-[[6-[4-Chloro-3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole

The title compound was made in an analogous manner to Intermediate 25using2-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole(Intermediate 19) and2-(4-chloro-3-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₇H₁₂ClF₂N₅O, 375.1; m/z found, 376.1 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 8.97 (d, J=1.9 Hz, 1H), 8.74-8.64 (m, 1H),8.45 (s, 1H), 8.17-8.09 (m, 1H), 8.10-8.02 (m, 1H), 7.80 (d, J=8.4 Hz,1H), 7.31 (t, J=54.1 Hz, 1H), 6.11 (s, 2H), 2.44 (s, 3H).

Example 107:2-[[6-[4-Chloro-3-(difluoromethyl)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole

The title compound was made in an analogous manner to Intermediate 25using2-((6-bromo-3-fluoro-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole(Intermediate 20) and2-(4-chloro-3-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₇H₁₁ClF₃N₅O, 393.1; m/z found, 394.1 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 9.02 (d, J=1.8 Hz, 1H), 8.77-8.71 (m, 1H),8.18-8.12 (m, 1H), 8.12-8.03 (m, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.32 (t,J=54.0 Hz, 1H), 6.01 (s, 2H), 2.46 (s, 3H).

Example 108:5-[[6-[3-Fluoro-5-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole

The title compound was prepared in a manner analogous to Intermediate 42using5-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-3-methyl-1,2,4-oxadiazole(Intermediate 55) and (3-fluoro-5-(trifluoromethyl)phenyl)boronic acid.MS (ESI): mass calcd. for C₁₇H₁₁F₄N₅O, 377.1; m/z found, 378.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 9.06 (d, J=2.0 Hz, 1H), 8.80-8.78 (m, 1H),8.49 (d, J=1.0 Hz, 1H), 8.16-8.07 (m, 2H), 7.82-7.77 (m, 1H), 6.21 (s,2H), 2.28 (s, 3H).

Example 109:5-[[6-[2-Fluoro-5-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole

The title compound was prepared in a manner analogous to Intermediate 42using5-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-3-methyl-1,2,4-oxadiazole(Intermediate 55) and (2-fluoro-5-(trifluoromethyl)phenyl)boronic acid.MS (ESI): mass calcd. for C₁₇H₁₁F₄N₅O, 377.1; m/z found, 378.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.84-8.81 (m, 1H), 8.61-8.58 (m, 1H),8.51-8.49 (m, 1H), 8.10-8.06 (m, 1H), 7.97-7.91 (m, 1H), 7.71-7.65 (m,1H), 6.21 (s, 2H), 2.28 (s, 3H).

Example 110:5-[[6-[4-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole

The title compound was prepared in a manner analogous to Intermediate 42using5-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-3-methyl-1,2,4-oxadiazole(Intermediate 55) and (4-fluoro-3-(trifluoromethyl)phenyl)boronic acid.MS (ESI): mass calcd. for C₁₇H₁₁F₄N₅O, 377.1; m/z found, 378.1 [M+H]⁺.¹H NMR (500 MHz, CDCl₃) δ 8.82 (d, J=1.9 Hz, 1H), 8.37 (d, J=1.0 Hz,1H), 7.93 (dd, J=1.9, 1.1 Hz, 1H), 7.88-7.79 (m, 2H), 7.38 (t, J=9.2 Hz,1H), 5.85 (s, 2H), 2.38 (s, 3H).

Example 111:5-[[6-[2-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole

The title compound was prepared in a manner analogous to Intermediate 42using5-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-3-methyl-1,2,4-oxadiazole(Intermediate 55) and (2-fluoro-3-(trifluoromethyl)phenyl)boronic acid.MS (ESI): mass calcd. for C₁₇H₁₁F₄N₅O, 377.1; m/z found, 378.1 [M+H]⁺.¹H NMR (400 MHz, DMSO-d₆) δ 8.81-8.78 (m, 1H), 8.60-8.58 (m, 1H),8.53-8.49 (m, 1H), 8.07-8.01 (m, 1H), 7.94-7.88 (m, 1H), 7.64-7.58 (m,1H), 6.22 (s, 2H), 2.28 (s, 3H).

Example 112:5-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 5-(chloromethyl)-3-methyl-1,2,4-oxadiazole. MS(ESI): mass calcd. for C₁₇H₁₂F₃N₅O₂, 375.1; m/z found, 376.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 8.96 (d, J=1.9 Hz, 1H), 8.66-8.59 (m, 1H),8.49-8.43 (m, 1H), 7.89-7.82 (m, 1H), 7.82-7.74 (m, 1H), 7.61 (dd,J=10.4, 8.6 Hz, 1H), 7.38 (t, J=73.2 Hz, 1H), 6.20 (s, 2H), 2.28 (s,3H).

Example 113:2-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole. MS(ESI): mass calcd. for C₁₇H₁₂F₃N₅O₂, 375.1; m/z found, 376.2 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 8.94 (d, J=1.9 Hz, 1H), 8.64-8.57 (m, 1H),8.49-8.41 (m, 1H), 7.89-7.82 (m, 1H), 7.82-7.74 (m, 1H), 7.62 (dd,J=10.5, 8.7 Hz, 1H), 7.38 (t, J=73.2 Hz, 1H), 6.09 (s, 2H), 2.45 (s,3H).

Example 114:3-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,2,4-oxadiazole

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 3-(chloromethyl)-5-methyl-1,2,4-oxadiazole. MS(ESI): mass calcd. for C₁₇H₁₂F₃N₅O₂, 375.1; m/z found, 376.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 8.93 (d, J=2.0 Hz, 1H), 8.65-8.54 (m, 1H), 8.40(s, 1H), 7.92-7.82 (m, 1H), 7.82-7.73 (m, 1H), 7.62 (dd, J=10.4, 8.8 Hz,1H), 7.39 (t, J=73.2 Hz, 1H), 5.94 (s, 2H), 2.52 (s, 3H).

Example 115:2-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-(trifluoromethyl)-1,3,4-oxadiazole

The title compound was prepared in a manner analogous to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and2-(chloromethyl)-5-(trifluoromethyl)-1,3,4-oxadiazole. MS (ESI): masscalcd. for C₁₇H₉F₆N₅O₂, 429.1; m/z found, 430.1 [M+H]⁺. ¹H NMR (600 MHz,CD₃OD) δ 8.86 (s, 1H), 8.48 (t, J=1.4 Hz, 1H), 8.35 (d, J=1.0 Hz, 1H),7.73 (dd, J=7.3, 2.3 Hz, 1H), 7.69 (ddd, J=8.5, 4.3, 2.3 Hz, 1H), 7.45(dd, J=10.3, 8.6 Hz, 1H), 6.98 (t, J=73.3 Hz, 1H), 6.19 (s, 2H).

Example 116:2-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole

The title compound was made in an analogous manner to Intermediate 25using2-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole(Intermediate 19) and2-(4-chloro-3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₇H₁₂ClF₂N₅O₂, 391.1; m/z found, 392.0[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 8.97 (d, J=1.9 Hz, 1H), 8.68-8.60(m, 1H), 8.46 (s, 1H), 7.86-7.82 (m, 1H), 7.80 (d, J=8.4 Hz, 1H), 7.76(dd, J=8.4, 1.9 Hz, 1H), 7.44 (t, J=73.2 Hz, 1H), 6.10 (s, 2H), 2.45 (s,3H).

Example 117:2-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole

The title compound was made in an analogous manner to Example 8 using6-(4-chloro-3-(difluoromethoxy)phenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine(Intermediate 31) and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole. MS(ESI): mass calcd. for C₁₇H₁₁ClF₃N₅O₂, 409.1; m/z found, 410.1 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 9.02 (d, J=1.8 Hz, 1H), 8.72-8.66 (m, 1H),7.88-7.84 (m, 1H), 7.82 (d, J=8.4 Hz, 1H), 7.77 (dd, J=8.5, 1.9 Hz, 1H),7.44 (t, J=73.1 Hz, 1H), 5.99 (s, 2H), 2.46 (s, 3H).

Example 118:2-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole

The title compound was prepared in a manner analogous to Example 8 using6-(2,4-difluoro-3-methylphenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate36) and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole. MS (ESI): masscalcd. for C₁₇H₁₃F₂N₅O, 341.1; m/z found, 342.1 [M+H]⁺. ¹H NMR (500 MHz,CD₃OD) δ 8.71 (t, J=1.9 Hz, 1H), 8.41-8.32 (m, 1H), 8.31 (d, J=1.0 Hz,1H), 7.55-7.42 (m, 1H), 7.11 (td, J=8.7, 1.5 Hz, 1H), 6.00 (s, 2H), 2.48(s, 3H), 2.30 (t, J=2.0 Hz, 3H).

Example 119:2-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-(trifluoromethyl)-1,3,4-oxadiazole

The title compound was prepared in a manner analogous to Example 8 using6-(2,4-difluoro-3-methylphenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate36) and 2-(chloromethyl)-5-(trifluoromethyl)-1,3,4-oxadiazole. MS (ESI):mass calcd. for C₁₇H₁₀F₅N₅O, 395.1; m/z found, 396.0 [M+H]⁺. ¹H NMR (500MHz, CD₃OD) δ 8.71 (t, J=1.9 Hz, 1H), 8.38-8.34 (m, 1H), 8.33 (d, J=1.0Hz, 1H), 7.46 (td, J=8.6, 6.2 Hz, 1H), 7.09 (td, J=8.7, 1.5 Hz, 1H),6.16 (s, 2H), 2.29 (t, J=2.0 Hz, 3H).

Example 120:4-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]thiadiazole

The title compound was prepared in a manner analogous to Example 1,using 4-(chloromethyl)-1,2,3-thiadiazole instead of2-(chloromethyl)pyrimidine hydrochloride. MS (ESI): mass calcd. forC₁₆H₁₀F₃N₅S, 361.1; m/z found, 362.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ9.15 (s, 1H), 8.98 (d, J=1.9 Hz, 1H), 8.83-8.81 (m, 1H), 8.42-8.40 (m,1H), 8.21-8.17 (m, 2H), 7.86-7.77 (m, 2H), 6.30 (s, 2H).

Example 121:2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazole

The title compound was prepared in a manner analogous to Example 8 using2-(chloromethyl)-1,3,4-thiadiazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₆H₁₀F₃N₅S, 361.1; m/z found, 362.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ9.10 (s, 1H), 8.81 (d, J=1.9 Hz, 1H), 8.37 (d, J=1.0 Hz, 1H), 8.00 (dd,J=1.8, 1.0 Hz, 1H), 7.88-7.81 (m, 1H), 7.72 (dt, J=7.5, 2.5 Hz, 1H),7.33-7.27 (m, 1H), 6.98 (t, J=54.8 Hz, 1H), 6.13 (s, 2H).

Example 122:2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole

The title compound was prepared in a manner analogous to Example 8 using2-(chloromethyl)-5-methyl-1,3,4-thiadiazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₇H₁₂F₃N₅S, 375.1; m/z found, 376.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.85 (d, J=1.9 Hz, 1H), 8.49 (dd, J=1.9, 1.0 Hz, 1H), 8.33 (d, J=1.0 Hz,1H), 8.07-7.91 (m, 2H), 7.42 (t, J=9.3 Hz, 1H), 7.08 (t, J=54.6 Hz, 1H),6.17 (s, 2H), 2.71 (s, 3H).

Example 123:2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethyl)-4-fluorophenyl)-3-fluoro-1H-pyrazolo[4,3-b]pyridine(Intermediate 30) and 2-(chloromethyl)-5-methyl-1,3,4-thiadiazole. MS(ESI): mass calcd. for C₁₇H₁₁F₄N₅S, 393.1; m/z found, 394.0 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.99 (d, J=1.9 Hz, 1H), 8.77-8.73 (m, 1H),8.13-8.07 (m, 2H), 7.64-7.57 (m, 1H), 7.31 (t, J=54.1 Hz, 1H), 6.13 (s,2H), 2.66 (s, 3H).

Example 124:2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-methyl-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole

The title compound was prepared in a manner analogous to Example 8 using6-(3-(difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine(Intermediate 35) and 2-(chloromethyl)-5-methyl-1,3,4-thiadiazole. MS(ESI): mass calcd. for C₁₈H₁₄F₃N₅S, 389.1; m/z found, 390.0 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.78 (d, J=1.9 Hz, 1H), 8.39 (d, J=1.9 Hz, 1H),8.05-7.85 (m, 2H), 7.47-7.29 (m, 1H), 7.26-6.84 (m, 1H), 6.06 (s, 2H),2.70 (s, 3H), 2.63 (s, 3H).

Example 125:2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-ethyl-1,3,4-thiadiazole

The title compound was prepared in a manner analogous to Example 8 using2-(chloromethyl)-5-ethyl-1,3,4-thiadiazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₈H₁₄F₃N₅S, 389.1; m/z found, 390.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.85 (d, J=1.9 Hz, 1H), 8.50 (dd, J=1.9, 1.0 Hz, 1H), 8.33 (d, J=1.0 Hz,1H), 8.06-7.90 (m, 2H), 7.42 (dd, J=10.0, 8.6 Hz, 1H), 7.08 (t, J=54.6Hz, 1H), 6.18 (s, 2H), 3.08 (q, J=7.6 Hz, 2H), 1.34 (t, J=7.6 Hz, 3H).

Example 126:5-((6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-N-methyl-1,3,4-thiadiazol-2-amine

The title compound was prepared in a manner analogous to Example 15using2-(6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)aceticacid (Intermediate 37). MS (ESI): mass calcd. for C₁₇H₁₃F₃NMS, 390.1;m/z found, 391.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.92 (d, J=1.9 Hz,1H), 8.66-8.62 (m, 1H), 8.44-8.42 (m, 1H), 8.11-8.06 (m, 2H), 7.63 (q,J=4.8 Hz, 1H), 7.61-7.56 (m, 1H), 7.30 (t, J=54.1 Hz, 1H), 5.99 (s, 2H),2.80 (d, J=4.8 Hz, 3H).

Example 127:2-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methoxy-1,3,4-thiadiazole

The title compound was made in an analogous manner to Example 8 using2-(chloromethyl)-5-methoxy-1,3,4-thiadiazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₇H₁₂F₃N₅OS, 391.1; m/z found, 392.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆)δ 8.94 (d, J=2.0 Hz, 1H), 8.73-8.63 (m, 1H), 8.47 (s, 1H), 8.15-8.01 (m,2H), 7.66-7.52 (m, 1H), 7.31 (t, J=54.1 Hz, 1H), 6.12 (s, 2H), 4.07 (s,3H).

Example 128:N-(5-((6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-1,3,4-thiadiazol-2-yl)acetamide

The title compound was prepared in a manner analogous to Example 19using5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazol-2-amine(Example 16). MS (ESI): mass calcd. for C₁₈H₁₃F₃N₆OS, 418.1; m/z found,419.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 12.51 (br s, 1H), 8.93 (d,J=2.0 Hz, 1H), 8.72-8.67 (m, 1H), 8.48-8.44 (m, 1H), 8.12-8.05 (m, 2H),7.62-7.54 (m, 1H), 7.30 (t, J=54.1 Hz, 1H), 6.17 (s, 2H), 2.13 (s, 3H).

Example 129:2-(Difluoromethyl)-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazole

The title compound was prepared in a manner analogous to Example 8 using2-(chloromethyl)-5-(difluoromethyl)-1,3,4-thiadiazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₇H₁₀F₅N₅S, 411.1; m/z found, 412.0 [M+H]⁺. ¹H NMR (500 MHz, CDCl₃) δ8.83 (d, J=1.9 Hz, 1H), 8.39 (d, J=1.0 Hz, 1H), 7.99 (dd, J=1.9, 1.0 Hz,1H), 7.85 (dd, J=6.4, 2.4 Hz, 1H), 7.77-7.69 (m, 1H), 7.31 (ddt, J=9.6,8.6, 1.1 Hz, 1H), 7.13-6.82 (m, 2H), 6.11 (s, 2H).

Example 130:2-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazole

The title compound was prepared in a manner analogous to Example 8 using2-(chloromethyl)-5-cyclopropyl-1,3,4-thiadiazole instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₉H₁₄F₃N₅S, 401.1; m/z found, 402.0 [M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ8.82 (d, J=1.9 Hz, 1H), 8.46 (dd, J=1.8, 1.0 Hz, 1H), 8.30 (d, J=1.0 Hz,1H), 8.06-7.87 (m, 2H), 7.40 (dd, J=9.9, 8.7 Hz, 1H), 7.07 (t, J=54.6Hz, 1H), 6.12 (s, 2H), 2.39 (tt, J=8.4, 4.8 Hz, 1H), 1.29-1.16 (m, 2H),1.02 (dt, J=7.2, 4.5 Hz, 2H).

Example 131:2-[[6-[4-Chloro-3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole

The title compound was prepared in a manner analogous to Example 9 usingIntermediate 24,2-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-thiadiazoleand2-(4-chloro-3-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₇H₁₂ClF₂N₅S, 391.0; m/z found, 392.0 [M+H]⁺.¹H NMR (500 MHz, CD₃OD) δ 8.87 (d, J=1.9 Hz, 1H), 8.53 (dd, J=1.9, 1.0Hz, 1H), 8.33 (d, J=1.0 Hz, 1H), 8.07 (d, J=2.2 Hz, 1H), 7.93 (ddd,J=8.3, 2.2, 1.1 Hz, 1H), 7.69 (dt, J=8.3, 1.1 Hz, 1H), 7.14 (t, J=54.6Hz, 1H), 6.18 (s, 2H), 2.71 (s, 3H).

Example 132:2-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole

The title compound was prepared in a manner analogous to Example 9 using2-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-thiadiazole(Intermediate 24) and 4-fluoro-3-methylphenylboronic acid. MS (ESI):mass calcd. for C₁₇H₁₄FN₅S, 339.1; m/z found, 340.0 [M+H]⁺. ¹H NMR (400MHz, CD₃OD) δ 8.82 (d, J=1.9 Hz, 1H), 8.45-8.36 (m, 1H), 8.30 (d, J=1.0Hz, 1H), 7.66 (d, J=7.2 Hz, 1H), 7.63-7.55 (m, 1H), 7.26-7.14 (m, 1H),6.15 (s, 2H), 2.71 (s, 3H), 2.38 (d, J=2.0 Hz, 3H).

Example 133:2-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole

The title compound was prepared in a manner analogous to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 2-(chloromethyl)-5-methyl-1,3,4-thiadiazole. MS(ESI): mass calcd. for C₁₇H₁₂F₃N₅OS, 391.1; m/z found, 392.1 [M+H]⁺. ¹HNMR (600 MHz, CD₃OD) δ 8.85 (d, J=1.9 Hz, 1H), 8.48 (dd, J=1.9, 1.0 Hz,1H), 8.34 (d, J=1.1 Hz, 1H), 7.77-7.66 (m, 2H), 7.45 (dd, J=10.3, 8.6Hz, 1H), 7.00 (t, J=73.3 Hz, 1H), 6.18 (s, 2H), 2.72 (s, 3H).

Example 134:2-[[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methoxy-1,3,4-thiadiazole

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 2-(chloromethyl)-5-methoxy-1,3,4-thiadiazole. MS(ESI): mass calcd. for C₁₇H₁₂F₃N₅O₂S, 407.1; m/z found, 408.1 [M+H]⁺.

Example 135:2-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole

The title compound was prepared in a manner analogous to Example 9 using2-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-thiadiazole(Intermediate 24) and2-(4-chloro-3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₇H₁₂ClF₂N₅OS, 407.0; m/z found, 408.0[M+H]⁺. ¹H NMR (500 MHz, CD₃OD) δ 8.85 (d, J=1.9 Hz, 1H), 8.49 (dd,J=1.9, 1.0 Hz, 1H), 8.33 (d, J=1.0 Hz, 1H), 7.76-7.61 (m, 3H), 7.02 (t,J=73.3 Hz, 1H), 6.17 (s, 2H), 2.71 (s, 3H).

Example 136:2-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole

The title compound was prepared in a manner analogous to Example 9 using2-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-thiadiazole(Intermediate 24) and (2,4-difluoro-3-methylphenyl)boronic acid. MS(ESI): mass calcd. for C₁₇H₁₃F₂N₅S, 357.1; m/z found, 358.0 [M+H]⁺. ¹HNMR (400 MHz, CD₃OD) δ 8.70 (s, 1H), 8.39-8.28 (m, 2H), 7.52-7.42 (m,1H), 7.15-7.04 (m, 1H), 6.15 (s, 2H), 2.71 (s, 3H), 2.30 (t, J=2.0 Hz,3H).

Example 137:6-(4-Methyl-2-thienyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate50) and 4-methylthiophene-2-boronic acid. MS (ESI): mass calcd. forC₁₇H₁₄N₄S, 306.1; m/z found, 307.1 [M+H]⁺. ¹H NMR (600 MHz, DMSO-d₆) δ8.85 (d, J=1.9 Hz, 1H), 8.61-8.59 (m, 1H), 8.54-8.52 (m, 1H), 8.49 (dd,J=4.8, 1.7 Hz, 1H), 8.35-8.34 (m, 1H), 7.67-7.64 (m, 1H), 7.60-7.58 (m,1H), 7.36-7.33 (m, 1H), 7.27-7.25 (m, 1H), 5.78 (s, 2H), 2.29-2.27 (m,3H).

Example 138:1-[(5-Methyl-3-pyridyl)methyl]-6-(4-methyl-2-thienyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((5-methylpyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 51) and 4-methylthiophene-2-boronic acid. MS (ESI): masscalcd. for C₁₈H₁₆N₄S, 320.1; m/z found, 321.0 [M+H]⁺. ¹H NMR (600 MHz,DMSO-d₆) δ 8.85 (d, J=1.9 Hz, 1H), 8.52-8.50 (m, 1H), 8.41-8.39 (m, 1H),8.35-8.32 (m, 2H), 7.60-7.58 (m, 1H), 7.49-7.47 (m, 1H), 7.28-7.25 (m,1H), 5.74 (s, 2H), 2.29-2.27 (m, 3H), 2.24 (s, 3H).

Example 139:6-(5-Methyl-2-thienyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate50) and using4,4,5,5-tetramethyl-2-(5-methylthiophen-2-yl)-1,3,2-dioxaborolane. MS(ESI): mass calcd. for C₁₇H₁₄N₄S, 306.1; m/z found, 307.0 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 8.83 (d, J=1.9 Hz, 1H), 8.61-8.58 (m, 1H), 8.49(dd, J=4.8, 1.6 Hz, 1H), 8.46-8.44 (m, 1H), 8.34-8.32 (m, 1H), 7.68-7.63(m, 1H), 7.55 (d, J=3.6 Hz, 1H), 7.35 (ddd, J=7.9, 4.8, 0.9 Hz, 1H),6.93-6.90 (m, 1H), 5.77 (s, 2H).

Example 140:5-[[6-(5-Chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile

The title compound was made in an analogous manner to Intermediate 41using 5-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)nicotinonitrile(Intermediate 21) and (5-chlorothiophen-2-yl)boronic acid. MS (ESI):mass calcd. for C₁₇H₁₀ClN₅S, 351.0; m/z found, 352.0 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 8.97 (d, J=2.0 Hz, 1H), 8.88 (d, J=1.9 Hz, 1H), 8.85 (d,J=1.9 Hz, 1H), 8.60-8.53 (m, 1H), 8.40 (s, 1H), 8.29-8.18 (m, 1H), 7.65(d, J=4.0 Hz, 1H), 7.28 (d, J=4.0 Hz, 1H), 5.83 (s, 2H).

Example 141:6-(3-Chloro-2-thienyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate50) and (3-chlorothiophen-2-yl)boronic acid. MS (ESI): mass calcd. forC₁₆H₁₁ClN₄S, 326.0; m/z found, 327.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.75 (d, J=1.9 Hz, 1H), 8.63-8.60 (m, 1H), 8.56-8.54 (m, 1H), 8.49 (dd,J=4.8, 1.6 Hz, 1H), 8.44-8.42 (m, 1H), 7.86 (d, J=5.4 Hz, 1H), 7.71-7.66(m, 1H), 7.38-7.33 (m, 1H), 7.28 (d, J=5.4 Hz, 1H), 5.81 (s, 2H).

Example 142:5-[[6-[5-(Difluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile

The title compound was made in an analogous manner to Intermediate 41using 5-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)nicotinonitrile(Intermediate 21) and2-(5-(difluoromethyl)thiophen-2-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Intermediate 12). MS (ESI): mass calcd. for C₁₅H₁₁F₂N₅S, 367.1; m/zfound, 368.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ 8.99-8.93 (m, 2H), 8.87(d, J=2.2 Hz, 1H), 8.72-8.67 (m, 1H), 8.42 (d, J=1.0 Hz, 1H), 8.28-8.22(m, 1H), 7.79-7.75 (m, 1H), 7.61-7.56 (m, 1H), 7.38 (t, J=55.2 Hz, 1H),5.85 (s, 2H).

Example 143:1-((6-Fluoropyridin-3-yl)methyl)-6-(5-(trifluoromethyl)thiophen-2-yl)-1H-pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 49) and (5-(trifluoromethyl)thiophen-2-yl)boronic acid. MS(ESI): mass calcd. for C₁₇H₁₀F₄FN₄S, 378.1; m/z found, 379.1 [M+H]⁺.

Example 144:5-[[6-[5-(Trifluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile

The title compound was made in an analogous manner to Intermediate 41using 5-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)nicotinonitrile(Intermediate 21) and (5-(trifluoromethyl)thiophen-2-yl)boronic acid. MS(ESI): mass calcd. for C₁₈H₁₀F₃N₅S, 385.1; m/z found, 386.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 8.99 (d, J=1.9 Hz, 1H), 8.97 (d, J=2.0 Hz, 1H),8.87 (d, J=2.2 Hz, 1H), 8.79-8.72 (m, 1H), 8.50-8.38 (m, 1H), 8.29-8.22(m, 1H), 7.92-7.78 (m, 2H), 5.85 (s, 2H).

Example 145:1-[(6-Fluoro-3-pyridyl)methyl]-6-(m-tolyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 49) and m-tolylboronic acid. MS (ESI): mass calcd. forC₁₉H₁₅FN₄, 318.1; m/z found, 319.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.87 (d, J=1.9 Hz, 1H), 8.63-8.60 (m, 1H), 8.38-8.36 (m, 1H), 8.33-8.31(m, 1H), 7.92 (td, J=8.3, 2.6 Hz, 1H), 7.68-7.66 (m, 1H), 7.65-7.61 (m,1H), 7.44 (t, J=7.6 Hz, 1H), 7.30-7.26 (m, 1H), 7.17-7.12 (m, 1H), 5.80(s, 2H), 2.43 (s, 3H).

Example 146:1-[(5-Fluoro-3-pyridyl)methyl]-6-(m-tolyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((5-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 54) and m-tolylboronic acid. MS (ESI): mass calcd. forC₁₉H₁₅FN₄, 318.1; m/z found, 319.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.88 (d, J=1.9 Hz, 1H), 8.62-8.60 (m, 1H), 8.52 (d, J=2.8 Hz, 1H), 8.47(t, J=1.8 Hz, 1H), 8.40-8.39 (m, 1H), 7.68-7.61 (m, 3H), 7.44 (t, J=7.6Hz, 1H), 7.30-7.26 (m, 1H), 5.85 (s, 2H), 2.43 (s, 3H).

Example 147:3-Fluoro-1-[(5-fluoro-3-pyridyl)methyl]-6-(m-tolyl)pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using6-bromo-3-fluoro-1-((5-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 15) and m-tolylboronic acid. MS (ESI): mass calcd. forC₁₉H₁₄F₂N₄, 336.1; m/z found, 337.3 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ8.92 (d, J=1.8 Hz, 1H), 8.70-8.62 (m, 1H), 8.57-8.51 (m, 1H), 8.52-8.44(m, 1H), 7.75-7.60 (m, 3H), 7.45 (t, J=7.6 Hz, 1H), 7.36-7.25 (m, 1H),5.72 (s, 2H), 2.43 (s, 3H).

Example 148:6-(4-Chlorophenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridinetrifluoroacetate Salt

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((5-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 54) and (4-chlorophenyl)boronic acid. MS (ESI): masscalcd. for C₁₈H₁₂ClFN₄, 338.1; m/z found, 339.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.90 (d, J=1.9 Hz, 1H), 8.68-8.66 (m, 1H), 8.52 (d, J=2.7 Hz,1H), 8.48 (t, J=1.8 Hz, 1H), 8.42-8.40 (m, 1H), 7.92-7.87 (m, 2H),7.69-7.65 (m, 1H), 7.64-7.60 (m, 2H), 5.84 (s, 2H).

Example 149:6-(4-Fluorophenyl)-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate53) and (4-fluorophenyl)boronic acid. MS (ESI): mass calcd. forC₁₈H₁₃FN₄, 304.1; m/z found, 305.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.87 (d, J=1.9 Hz, 1H), 8.51-8.48 (m, 2H), 8.37-8.36 (m, 1H), 7.90-7.85(m, 2H), 7.74 (td, J=7.7, 1.8 Hz, 1H), 7.41-7.35 (m, 2H), 7.30-7.27 (m,1H), 7.11-7.08 (m, 1H), 5.86 (s, 2H).

Example 150:6-(4-Fluorophenyl)-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using6-bromo-1-((5-methoxypyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 14) and (4-fluorophenyl)boronic acid. MS (ESI): masscalcd. for C₁₉H₁₅FN₄O, 334.1; m/z found, 335.2 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.87 (d, J=1.9 Hz, 1H), 8.61 (dd, J=2.0, 1.0 Hz, 1H), 8.38(d, J=1.0 Hz, 1H), 8.24-8.19 (m, 1H), 8.19-8.14 (m, 1H), 7.93-7.86 (m,2H), 7.43-7.36 (m, 2H), 7.34-7.30 (m, 1H), 5.77 (s, 2H), 3.78 (s, 3H).

Example 151:1-[[5-(Difluoromethoxy)-3-pyridyl]methyl]-6-(4-fluorophenyl)pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using6-bromo-1-((5-(difluoromethoxy)pyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 17) and (4-fluorophenyl)boronic acid. MS (ESI): masscalcd. for C₁₉H₁₃F₃N₄O, 370.1; m/z found, 371.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.88 (d, J=1.9 Hz, 1H), 8.66-8.61 (m, 1H), 8.51-8.46 (m, 1H),8.44-8.41 (m, 1H), 8.41-8.38 (m, 1H), 7.93-7.85 (m, 2H), 7.65-7.60 (m,1H), 7.43-7.36 (m, 2H), 7.27 (t, J=73.3 Hz, 1H), 5.83 (s, 2H).

Example 152:6-(3-Fluorophenyl)-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate53) and (3-fluorophenyl)boronic acid. MS (ESI): mass calcd. forC₁₈H₁₃FN₄, 304.1; m/z found, 305.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.93 (d, J=1.9 Hz, 1H), 8.60-8.58 (m, 1H), 8.50-8.48 (m, 1H), 8.39-8.38(m, 1H), 7.77-7.68 (m, 3H), 7.61-7.55 (m, 1H), 7.31-7.26 (m, 2H),7.12-7.09 (m, 1H), 5.87 (s, 2H).

Example 153:6-(2-Fluorophenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((5-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 54) and (2-fluorophenyl)boronic acid. MS (ESI): masscalcd. for C₁₈H₁₂F₂N₄, 322.1; m/z found, 323.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.73 (t, J=1.9 Hz, 1H), 8.57-8.55 (m, 1H), 8.52 (d, J=2.8 Hz,1H), 8.48-8.46 (m, 1H), 8.44-8.42 (m, 1H), 7.73-7.65 (m, 2H), 7.56-7.50(m, 1H), 7.44-7.37 (m, 2H), 5.84 (s, 2H).

Example 154:6-(3-Methoxyphenyl)-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate53) and (3-methoxyphenyl)boronic acid. MS (ESI): mass calcd. forC₁₉H₁₆N₄O, 316.1; m/z found, 317.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.90 (d, J=1.9 Hz, 1H), 8.51-8.48 (m, 2H), 8.37-8.36 (m, 1H), 7.74 (td,J=7.7, 1.8 Hz, 1H), 7.47-7.42 (m, 1H), 7.40-7.35 (m, 2H), 7.30-7.27 (m,1H), 7.11-7.08 (m, 1H), 7.04-7.00 (m, 1H), 5.87 (s, 2H), 3.86 (s, 3H).

Example 155:1-[(6-Fluoro-3-pyridyl)methyl]-6-(3-methoxyphenyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 49) and (3-methoxyphenyl)boronic acid. MS (ESI): masscalcd. for C₁₉H₁₅FN₄O, 334.1; m/z found, 335.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.90 (d, J=1.9 Hz, 1H), 8.64-8.62 (m, 1H), 8.39-8.37 (m, 1H),8.33-8.31 (m, 1H), 7.92 (td, J=8.2, 2.6 Hz, 1H), 7.49-7.44 (m, 1H),7.42-7.38 (m, 2H), 7.16-7.13 (m, 1H), 7.04 (ddd, J=8.2, 2.6, 1.0 Hz,1H), 5.80 (s, 2H), 3.87 (s, 3H).

Example 156:6-[3-(Difluoromethyl)phenyl]-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate53) and (3-(difluoromethyl)phenyl)boronic acid. MS (ESI): mass calcd.for C₁₉H₁₄F₂N₄, 336.1; m/z found, 337.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.92 (d, J=1.9 Hz, 1H), 8.61-8.59 (m, 1H), 8.50-8.48 (m, 1H),8.40-8.38 (m, 1H), 8.04-7.99 (m, 2H), 7.75 (td, J=7.7, 1.8 Hz, 1H),7.72-7.64 (m, 2H), 7.31-7.27 (m, 1H), 7.13 (t, J=55.8 Hz, 1H), 7.11-7.08(m, 1H), 5.89 (s, 2H).

Example 157:5-[[6-[3-(Difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile

The title compound was made in an analogous manner to Intermediate 25using 5-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)nicotinonitrile(Intermediate 21) and (3-(difluoromethyl)phenyl)boronic acid. MS (ESI):mass calcd. for C₂₀H₁₃F₂N₅, 361.1; m/z found, 362.1 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 8.96 (d, J=2.0 Hz, 1H), 8.93 (d, J=1.9 Hz, 1H), 8.87 (d,J=2.1 Hz, 1H), 8.76-8.67 (m, 1H), 8.43 (s, 1H), 8.31-8.21 (m, 1H),8.12-7.98 (m, 2H), 7.78-7.60 (m, 2H), 7.14 (t, J=55.8 Hz, 1H), 5.88 (s,2H).

Example 158:1-[(5-Chloro-3-pyridyl)methyl]-6-[3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using6-bromo-1-((5-chloropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 18) and (3-(difluoromethyl)phenyl)boronic acid. MS (ESI):mass calcd. for C₁₉H₁₃ClF₂N₄, 370.1; m/z found, 371.1 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 8.93 (d, J=1.9 Hz, 1H), 8.80-8.67 (m, 1H),8.63-8.48 (m, 2H), 8.43 (s, 1H), 8.12-7.98 (m, 2H), 7.93-7.81 (m, 1H),7.77-7.63 (m, 2H), 7.14 (t, J=55.8 Hz, 1H), 5.84 (s, 2H).

Example 159:6-[3-(Difluoromethoxy)phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((5-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 54) and (3-(difluoromethoxy)phenyl)boronic acid. MS (ESI):mass calcd. for C₁₉H₁₃F₃N₄O, 370.1; m/z found, 371.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.93 (d, J=1.9 Hz, 1H), 8.70-8.68 (m, 1H), 8.52 (d,J=2.8 Hz, 1H), 8.48 (t, J=1.8 Hz, 1H), 8.42 (d, J=1.0 Hz, 1H), 7.76-7.73(m, 1H), 7.70-7.64 (m, 2H), 7.61 (t, J=8.0 Hz, 1H), 7.38 (t, J=74.0 Hz,1H), 7.30-7.26 (m, 1H), 5.85 (s, 2H).

Example 160:6-[3-(1,1-Difluoroethyl)phenyl]-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(1,1-difluoroethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate29) and 3-(chloromethyl)-5-methylpyridine. MS (ESI): mass calcd. forC₂₁H₁₈F₂N₄, 364.2; m/z found, 365.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.93 (d, J=1.9 Hz, 1H), 8.69 (dd, J=2.0, 1.0 Hz, 1H), 8.43-8.40 (m, 1H),8.40 (d, J=0.9 Hz, 1H), 8.35-8.32 (m, 1H), 8.01-7.95 (m, 2H), 7.70-7.63(m, 2H), 7.53-7.50 (m, 1H), 5.78 (s, 2H), 2.24 (s, 3H), 2.07 (t, J=18.9Hz, 3H).

Example 161:6-[3-(1,1-Difluoroethyl)phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(1,1-difluoroethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate29) and 3-(chloromethyl)-5-fluoropyridine. MS (ESI): mass calcd. forC₂₀H₁₅F₃N₄, 368.1; m/z found, 369.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.94 (d, J=1.9 Hz, 1H), 8.71 (dd, J=2.0, 1.0 Hz, 1H), 8.52 (d, J=2.8 Hz,1H), 8.49-8.45 (m, 1H), 8.43 (d, J=1.0 Hz, 1H), 8.02-7.95 (m, 2H),7.72-7.62 (m, 3H), 5.86 (s, 2H), 2.06 (t, J=18.9 Hz, 3H).

Example 162:1-(2-Pyridylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 8,using 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 42) and 2-(bromomethyl)pyridine hydrobromide. MS (ESI):mass calcd. for C₁₉H₁₃F₃N₄, 354.1; m/z found, 355.1 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 8.82 (d, J=2.02 Hz, 1H), 8.59 (dt, J=4.84, 1.19 Hz, 1H),8.36 (d, J=1.16 Hz, 1H), 7.97 (dd, J=1.88, 1.01 Hz, 1H), 7.85 (s, 1H),7.81 (d, J=7.51 Hz, 1H), 7.74-7.67 (m, 1H), 7.66-7.56 (m, 2H), 7.23(ddd, J=7.51, 4.91, 0.87 Hz, 1H), 7.07 (d, J=7.80 Hz, 1H), 5.79 (s, 2H).

Example 163:1-(3-Pyridylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridinehydrochloride Salt

The title compound was prepared in a manner analogous to Example 8,using 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 42) and 3-(bromomethyl)pyridine hydrobromide. MS (ESI):mass calcd. for C₁₉H₁₃F₃N₄, 354.1; m/z found, 355.0 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 9.01 (d, J=2.02 Hz, 1H), 8.92 (s, 1H), 8.86-8.76 (m,2H), 8.49 (d, J=0.87 Hz, 1H), 8.31 (d, J=8.09 Hz, 1H), 8.25-8.14 (m,2H), 7.90 (dd, J=7.95, 5.64 Hz, 1H), 7.88-7.76 (m, 2H), 6.00 (s, 2H).

Example 164:1-(4-Pyridylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridinehydrochloride Salt

The title compound was prepared in a manner analogous to Example 8,using 6-(3-(trifluoromethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 42) and 4-(bromomethyl)pyridine hydrobromide. MS (ESI):mass calcd. for C₁₉H₁₃F₃N₄, 354.1; m/z found, 355.1 [M+H]⁺. ¹H NMR (500MHz, CDCl₃) δ 8.86 (d, J=1.73 Hz, 1H), 8.66-8.46 (m, 2H), 8.40 (d,J=0.87 Hz, 1H), 7.84 (s, 1H), 7.78 (d, J=7.80 Hz, 1H), 7.76-7.73 (m,1H), 7.73-7.68 (m, 1H), 7.67-7.61 (m, 1H), 7.06 (d, J=6.07 Hz, 2H), 5.69(s, 2H).

Example 165:1-[(6-Methyl-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 1,using 5-(chloromethyl)-2-methylpyridine hydrochloride instead of2-(chloromethyl)pyrimidine hydrochloride. MS (ESI): mass calcd. forC₂₀H₁₅F₃N₄, 368.1; m/z found, 369.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.95 (d, J=1.9 Hz, 1H), 8.76-8.74 (m, 1H), 8.51-8.49 (m, 1H), 8.40-8.38(m, 1H), 8.20-8.14 (m, 2H), 7.85-7.76 (m, 2H), 7.59 (dd, J=8.0, 2.4 Hz,1H), 7.21-7.17 (m, 1H), 5.76 (s, 2H), 2.41 (s, 3H).

Example 166:1-[(2-Methyl-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((2-methylpyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 47) and (3-(trifluoromethyl)phenyl)boronic acid. MS (ESI):mass calcd. for C₂₀H₁₅F₃N₄, 368.1; m/z found, 369.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.97 (d, J=1.9 Hz, 1H), 8.70-8.66 (m, 1H), 8.45-8.43 (m,1H), 8.36-8.34 (m, 1H), 8.18-8.14 (m, 2H), 7.87-7.75 (m, 2H), 7.16-7.09(m, 2H), 5.83 (s, 2H), 2.56 (s, 3H).

Example 167:1-[(5-Methyl-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 1,using 3-(chloromethyl)-5-methylpyridine hydrochloride instead of2-(chloromethyl)pyrimidine hydrochloride. MS (ESI): mass calcd. forC₂₀H₁₅F₃N₄, 368.1; m/z found, 369.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.95 (d, J=1.9 Hz, 1H), 8.76-8.74 (m, 1H), 8.43-8.39 (m, 2H), 8.34-8.32(m, 1H), 8.20-8.15 (m, 2H), 7.85-7.77 (m, 2H), 7.53-7.50 (m, 1H), 5.77(s, 2H), 2.26-2.22 (m, 3H).

Example 168:1-[(4-Methyl-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridinetrifluoroacetate Salt

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((4-methylpyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 52) and (3-(trifluoromethyl)phenyl)boronic acid. MS (ESI):mass calcd. for C₂₀H₁₅F₃N₄, 368.1; m/z found, 369.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 9.00 (d, J=1.9 Hz, 1H), 8.76-8.73 (m, 1H), 8.64 (d,J=5.6 Hz, 1H), 8.47-8.45 (m, 1H), 8.38 (s, 1H), 8.21-8.15 (m, 2H),7.87-7.77 (m, 2H), 7.73 (d, J=5.6 Hz, 1H), 5.94 (s, 2H), 2.53 (s, 3H).

Example 169:1-[(6-Fluoro-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 49) and (3-(trifluoromethyl)phenyl)boronic acid. MS (ESI):mass calcd. for C₁₉H₁₂F₄N₄, 372.1; m/z found, 373.0 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.96 (d, J=1.9 Hz, 1H), 8.79-8.77 (m, 1H), 8.4-8.40 (m,1H), 8.34-8.31 (m, 1H), 8.21-8.16 (m, 2H), 7.93 (td, J=8.2, 2.6 Hz, 1H),7.85-7.77 (m, 2H), 7.16-7.13 (m, 1H), 5.82 (s, 2H).

Example 170:1-[(2-Fluoro-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 1,using 3-(chloromethyl)-2-fluoropyridine instead of2-(chloromethyl)pyrimidine hydrochloride. MS (ESI): mass calcd. forC₁₉H₁₂F₄N₄, 372.1; m/z found, 373.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.98 (d, J=2.0 Hz, 1H), 8.76-8.72 (m, 1H), 8.44-8.41 (m, 1H), 8.21-8.15(m, 3H), 7.86-7.76 (m, 2H), 7.69-7.62 (m, 1H), 7.34-7.29 (m, 1H), 5.85(s, 2H).

Example 171:1-[(5-Fluoro-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 1,using (5-fluoropyridin-3-yl)methyl methanesulfonate (Intermediate 7)instead of 2-(chloromethyl)pyrimidine hydrochloride. MS (ESI): masscalcd. for C₁₉H₁₂F₄N₄, 372.1; m/z found, 373.0 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.97 (d, J=1.9 Hz, 1H), 8.78-8.75 (m, 1H), 8.52 (d, J=2.8 Hz,1H), 8.48 (t, J=1.8 Hz, 1H), 8.44-8.43 (m, 1H), 8.21-8.16 (m, 2H),7.85-7.77 (m, 2H), 7.69-7.64 (m, 1H), 5.87 (s, 2H).

Example 172:1-[(2-Methoxy-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridinetrifluoroacetate Salt

The title compound was prepared in a manner analogous to Example 1,using 3-(chloromethyl)-2-methoxypyridine instead of2-(chloromethyl)pyrimidine hydrochloride. MS (ESI): mass calcd. forC₂₀H₁₅F₃N₄O, 384.1; m/z found, 385.1 [M+H]₊. ¹H NMR (500 MHz, DMSO-d₆) δ8.97 (d, J=1.9 Hz, 1H), 8.69-8.67 (m, 1H), 8.41-8.39 (m, 1H), 8.20-8.16(m, 2H), 8.10 (dd, J=5.0, 1.9 Hz, 1H), 7.84-7.76 (m, 2H), 7.19-7.15 (m,1H), 6.92 (dd, J=7.3, 5.0 Hz, 1H), 5.72 (s, 2H), 3.88 (s, 3H).

Example 173:1-[(5-Methoxy-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 1,using 3-(chloromethyl)-5-methoxypyridine hydrochloride instead of2-(chloromethyl)pyrimidine hydrochloride. MS (ESI): mass calcd. forC₂₀H₁₅F₃N₄O, 384.1; m/z found, 385.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.96 (d, J=1.9 Hz, 1H), 8.78-8.75 (m, 1H), 8.43-8.41 (m, 1H), 8.22 (d,J=2.8 Hz, 1H), 8.20-8.16 (m, 3H), 7.85-7.77 (m, 2H), 7.35-7.33 (m, 1H),5.80 (s, 2H), 3.78 (s, 3H).

Example 174:6-[3-(Trifluoromethyl)phenyl]-1-[[6-trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 1,using (6-(trifluoromethyl)pyridin-3-yl)methyl methanesulfonate(Intermediate 9) instead of 2-(chloromethyl)pyrimidine hydrochloride. MS(ESI): mass calcd. for C₂₀H₁₂FN₄, 422.1; m/z found, 423.0 [M+H]⁺. ¹H NMR(400 MHz, DMSO-d₆) δ 8.98 (d, J=1.9 Hz, 1H), 8.81-8.77 (m, 2H),8.46-8.45 (m, 1H), 8.21-8.15 (m, 2H), 7.94-7.76 (m, 4H), 5.95 (s, 2H).

Example 175:6-[3-(Trifluoromethyl)phenyl]-1-[[5-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 1,using (5-(trifluoromethyl)pyridin-3-yl)methyl methanesulfonate(Intermediate 10) instead of 2-(chloromethyl)pyrimidine hydrochloride.MS (ESI): mass calcd. for C₂₀H₁₂FN₄, 422.1; m/z found, 423.0 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.97 (d, J=1.9 Hz, 1H), 8.94-8.92 (m, 1H),8.88-8.86 (m, 1H), 8.81-8.79 (m, 1H), 8.46-8.44 (m, 1H), 8.23-8.16 (m,3H), 7.86-7.77 (m, 2H), 5.93 (s, 2H).

Example 176:6-[3-(Trifluoromethyl)phenyl]-1-[[4-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 1,using (4-(trifluoromethyl)pyridin-3-yl)methyl methanesulfonate instead(Intermediate 11) of 2-(chloromethyl)pyrimidine hydrochloride. MS (ESI):mass calcd. for C₂₀H₁₂F₆N₄, 422.1; m/z found, 423.0 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 9.00 (d, J=1.9 Hz, 1H), 8.82 (d, J=5.1 Hz, 1H),8.76-8.74 (m, 1H), 8.46-8.43 (m, 1H), 8.32 (s, 1H), 8.22-8.16 (m, 2H),7.87-7.77 (m, 3H), 6.01 (s, 2H).

Example 177:6-(4-Fluoro-3-methyl-phenyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate50) and 4-fluoro-3-methylphenyl)boronic acid. MS (ESI): mass calcd. forC₁₉H₁₅FN₄, 318.1; m/z found, 319.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.86 (d, J=2.0 Hz, 1H), 8.63-8.58 (m, 2H), 8.50-8.47 (m, 1H), 8.38-8.36(m, 1H), 7.82-7.76 (m, 1H), 7.72-7.65 (m, 2H), 7.37-7.28 (m, 2H), 5.79(s, 2H), 2.37-3.31 (m, 3H).

Example 178:3-Fluoro-6-(4-fluoro-3-methyl-phenyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using 6-bromo-3-fluoro-1-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 16) and (4-fluoro-3-methylphenyl)boronic acid. MS (ESI):mass calcd. for C₁₉H₁₄F₂N₄, 336.1; m/z found, 337.3 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 8.91 (d, J=1.8 Hz, 1H), 8.69-8.63 (m, 1H), 8.64-8.58 (m,1H), 8.51 (dd, J=4.9, 1.7 Hz, 1H), 7.86-7.77 (m, 1H), 7.76-7.66 (m, 2H),7.42-7.28 (m, 2H), 5.67 (s, 2H), 2.38-2.31 (m, 3H).

Example 179:6-(4-Fluoro-3-methyl-phenyl)-1-[(2-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((2-methylpyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 47) and (4-fluoro-3-methylphenyl)boronic acid. MS (ESI):mass calcd. for C₂₀H₁₇FN₄, 332.1; m/z found, 333.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.88 (d, J=1.9 Hz, 1H), 8.52-8.49 (m, 1H), 8.40-8.39 (m,1H), 8.36-8.34 (m, 1H), 7.78-7.75 (m, 1H), 7.69-7.65 (m, 1H), 7.33-7.27(m, 1H), 7.15-7.07 (m, 2H), 5.80 (s, 2H), 2.55 (s, 3H), 2.35-2.32 (m,3H).

Example 180:6-(4-Fluoro-3-methyl-phenyl)-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridinetrifluoroacetate Salt

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((5-methylpyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 51) and (4-fluoro-3-methylphenyl)boronic acid. MS (ESI):mass calcd. for C₂₀H₁₇FN₄, 332.1; m/z found, 333.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.90-8.86 (m, 1H), 8.69-8.51 (m, 3H), 8.42-8.39 (m, 1H),7.91 (s, 1H), 7.81-7.77 (m, 1H), 7.72-7.67 (m, 1H), 7.35-7.30 (m, 1H),5.84 (s, 2H), 2.36-2.33 (m, 6H).

Example 181:6-(4-Fluoro-3-methyl-phenyl)-1-[(4-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridinetrifluoroacetate Salt

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((4-methylpyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 52) and (4-fluoro-3-methylphenyl)boronic acid. MS (ESI):mass calcd. for C₂₀H₁₇FN₄, 332.1; m/z found, 333.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.90 (d, J=1.9 Hz, 1H), 8.63 (d, J=5.5 Hz, 1H),8.60-8.58 (m, 1H), 8.42-8.41 (m, 1H), 8.36 (s, 1H), 7.81-7.77 (m, 1H),7.74-7.67 (m, 2H), 7.35-7.30 (m, 1H), 5.91 (s, 2H), 2.53 (s, 3H),2.36-2.33 (m, 3H).

Example 182:6-(4-Fluoro-3-methyl-phenyl)-1-[(6-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 49) and (4-fluoro-3-methylphenyl)boronic acid. MS (ESI):mass calcd. for C₁₉H₁₄F₂N₄, 336.1; m/z found, 337.1 [M+H]⁺. ¹H NMR (400MHz, DMSO-d₆) δ 8.87 (d, J=1.9 Hz, 1H), 8.63-8.60 (m, 1H), 8.38-8.36 (m,1H), 8.33-8.31 (m, 1H), 7.92 (td, J=8.2, 2.6 Hz, 1H), 7.82-7.77 (m, 1H),7.73-7.66 (m, 1H), 7.36-7.28 (m, 1H), 7.15 (dd, J=8.5, 2.8 Hz, 1H), 5.79(s, 2H), 2.36-2.33 (m, 3H).

Example 183:6-(4-Fluoro-3-methyl-phenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((5-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 54) and (4-fluoro-3-methylphenyl)boronic acid. MS (ESI):mass calcd. for C₁₉H₁₄F₂N₄, 336.1; m/z found, 337.2 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.87 (d, J=1.9 Hz, 1H), 8.62-8.60 (m, 1H), 8.52 (d,J=2.7 Hz, 1H), 8.47 (t, J=1.8 Hz, 1H), 8.40 (d, J=1.0 Hz, 1H), 7.82-7.77(m, 1H), 7.72-7.63 (m, 2H), 7.34-7.29 (m, 1H), 5.84 (s, 2H), 2.36-2.33(m, 3H).

Example 184:6-(3,5-Difluorophenyl)-1-[(4-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridinetrifluoroacetate Salt

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((4-methylpyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 52) and (3,5-difluorophenyl)boronic acid. MS (ESI): masscalcd. for C₁₉H₁₄F₂N₄, 336.1; m/z found, 337.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 9.00 (d, J=1.9 Hz, 1H), 8.76-8.73 (m, 1H), 8.62 (d, J=5.5 Hz,1H), 8.47-8.44 (m, 1H), 8.38 (s, 1H), 7.73-7.65 (m, 3H), 7.36 (tt,J=9.3, 2.3 Hz, 1H), 5.91 (s, 2H), 2.53 (s, 3H).

Example 185:6-(3,5-Difluorophenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((5-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 54) and (3,5-difluorophenyl)boronic acid. MS (ESI): masscalcd. for C₁₈H₁₁F₃N₄, 340.1; m/z found, 341.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.97 (d, J=1.9 Hz, 1H), 8.78-8.76 (m, 1H), 8.52 (d, J=2.8 Hz,1H), 8.50-8.48 (m, 1H), 8.44-8.42 (m, 1H), 7.73-7.64 (m, 3H), 7.35 (tt,J=9.2, 2.3 Hz, 1H), 5.84 (s, 2H).

Example 186:6-(3,4-Difluorophenyl)-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridinetrifluoroacetate Salt

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate53) and (3,4-difluorophenyl)boronic acid. MS (ESI): mass calcd. forC₁₈H₁₂F₂N₄, 322.1; m/z found, 323.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.92 (d, J=1.9 Hz, 1H), 8.61-8.59 (m, 1H), 8.53-8.50 (m, 1H), 8.40-8.38(m, 1H), 7.99 (ddd, J=12.2, 7.7, 2.3 Hz, 1H), 7.79 (td, J=7.7, 1.8 Hz,1H), 7.74-7.69 (m, 1H), 7.65-7.58 (m, 1H), 7.35-7.31 (m, 1H), 7.15-7.12(m, 1H), 5.88 (s, 2H).

Example 187:6-(3,4-Difluorophenyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridinetrifluoroacetate Salt

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate50) and (3,4-difluorophenyl)boronic acid. MS (ESI): mass calcd. forC₁₈H₁₂F₂N₄, 322.1; m/z found, 323.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.93 (d, J=1.9 Hz, 1H), 8.77-8.74 (m, 1H), 8.71-8.69 (m, 1H), 8.65-8.61(m, 1H), 8.44-8.41 (m, 1H), 8.04-7.96 (m, 2H), 7.77-7.71 (m, 1H),7.68-7.58 (m, 2H), 5.86 (s, 2H).

Example 188:6-(3,4-Difluorophenyl)-1-[(2-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((2-methylpyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 47) and (3,4-difluorophenyl)boronic acid. MS (ESI): masscalcd. for C₁₉H₁₄F₂N₄, 336.1; m/z found, 337.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.93 (d, J=2.0 Hz, 1H), 8.61-8.59 (m, 1H), 8.43-8.41 (m, 1H),8.36-8.34 (m, 1H), 7.99 (ddd, J=12.2, 7.7, 2.4 Hz, 1H), 7.74-7.69 (m,1H), 7.66-7.58 (m, 1H), 7.16-7.09 (m, 2H), 5.79 (s, 2H), 2.56 (s, 3H).

Example 189:6-(3,4-Difluorophenyl)-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((5-methylpyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 51) and (3,4-difluorophenyl)boronic acid. MS (ESI): masscalcd. for C₁₉H₁₄F₂N₄, 336.1; m/z found, 337.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.91 (d, J=1.9 Hz, 1H), 8.69-8.67 (m, 1H), 8.43-8.41 (m, 1H),8.40-8.38 (m, 1H), 8.34-8.32 (m, 1H), 8.01 (ddd, J=12.2, 7.7, 2.3 Hz,1H), 7.76-7.71 (m, 1H), 7.66-7.60 (m, 1H), 7.53-7.50 (m, 1H), 5.74 (s,2H), 2.24 (d, J=0.8 Hz, 3H).

Example 190:6-(3,4-Difluorophenyl)-1-[(4-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridinetrifluoroacetate Salt

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((4-methylpyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 52) and (3,4-difluorophenyl)boronic acid. MS (ESI): masscalcd. for C₁₉H₁₄F₂N₄, 336.1; m/z found, 337.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.95 (d, J=1.9 Hz, 1H), 8.70-8.63 (m, 2H), 8.46-8.44 (m, 1H),8.40 (s, 1H), 8.00 (ddd, J=12.1, 7.8, 2.3 Hz, 1H), 7.79-7.71 (m, 2H),7.68-7.60 (m, 1H), 5.92 (s, 2H), 2.55 (s, 3H).

Example 191:6-(3,4-Difluorophenyl)-1-[(6-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 49) and (3,4-difluorophenyl)boronic acid. MS (ESI): masscalcd. for C₁₈H₁₁F₃N₄, 340.1; m/z found, 341.0 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.91 (d, J=1.9 Hz, 1H), 8.72-8.68 (m, 1H), 8.40-8.38 (d,J=1.0 Hz, 1H), 8.34-8.32 (m, 1H), 8.01 (ddd, J=12.2, 7.8, 2.3 Hz, 1H),7.94 (td, J=8.2, 2.5 Hz, 1H), 7.77-7.72 (m, 1H), 7.67-7.59 (m, 1H), 7.15(dd, J=8.5, 2.8 Hz, 1H), 5.79 (s, 2H).

Example 192:6-(3,4-Difluorophenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridinetrifluoroacetate Salt

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((5-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 54) and (3,4-difluorophenyl)boronic acid. MS (ESI): masscalcd. for C₁₈H₁₁F₃N₄, 340.1; m/z found, 341.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.93 (d, J=1.9 Hz, 1H), 8.72-8.69 (m, 1H), 8.52 (d, J=2.8 Hz,1H), 8.49-8.48 (m, 1H), 8.43-8.41 (m, 1H), 8.01 (ddd, J=12.2, 7.7, 2.3Hz, 1H), 7.77-7.72 (m, 1H), 7.70-7.60 (m, 2H), 5.83 (s, 2H).

Example 193:6-(3,4-Difluorophenyl)-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using6-bromo-1-((5-methoxypyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 14) and (3,4-difluorophenyl)boronic acid. MS (ESI): masscalcd. for C₁₉H₁₄F₂N₄O, 352.1; m/z found, 353.2 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 8.91 (d, J=1.9 Hz, 1H), 8.73-8.64 (m, 1H), 8.42-8.36 (m, 1H),8.22 (d, J=2.8 Hz, 1H), 8.19-8.14 (m, 1H), 8.06-7.95 (m, 1H), 7.78-7.69(m, 1H), 7.69-7.56 (m, 1H), 7.37-7.28 (m, 1H), 5.76 (s, 2H), 3.78 (s,3H).

Example 194:1-[[5-(Difluoromethoxy)-3-pyridyl]methyl]-6-(3,4-difluorophenyl)pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using6-bromo-1-((5-(difluoromethoxy)pyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 17) and (3,4-difluorophenyl)boronic acid. MS (ESI): masscalcd. for C₁₉H₁₂F₄N₄O, 388.1; m/z found, 389.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.92 (d, J=1.9 Hz, 1H), 8.71-8.67 (m, 1H), 8.51-8.46 (m, 1H),8.44-8.41 (m, 1H), 8.42-8.41 (m, 1H), 8.04-7.96 (m, 1H), 7.77-7.70 (m,1H), 7.68-7.59 (m, 2H), 7.28 (t, J=73.2 Hz, 1H), 5.83 (s, 2H).

Example 195:6-(3-Chloro-4-fluoro-phenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((5-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 54) and (3-chloro-4-fluorophenyl)boronic acid. MS (ESI):mass calcd. for C₁₈H₁₁ClF₂N₄, 356.1; m/z found, 357.1 [M+H]⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 8.92 (d, J=1.9 Hz, 1H), 8.72-8.69 (m, 1H), 8.52 (d,J=2.7 Hz, 1H), 8.49-8.47 (m, 1H), 8.43-8.40 (m, 1H), 8.13 (dd, J=7.1,2.4 Hz, 1H), 7.90 (ddd, J=8.5, 4.6, 2.4 Hz, 1H), 7.69-7.64 (m, 1H),7.63-7.58 (m, 1H), 5.83 (s, 2H).

Example 196:6-(3-Chloro-4-fluoro-phenyl)-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using6-bromo-1-((5-methoxypyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 14) and (3-chloro-4-fluorophenyl)boronic acid. MS (ESI):mass calcd. for C₁₉H₁₄ClFN₄O, 368.1; m/z found, 369.1 [M+H]⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 8.90 (d, J=1.9 Hz, 1H), 8.71-8.69 (m, 1H), 8.40 (d,J=0.9 Hz, 1H), 8.22 (d, J=2.8 Hz, 1H), 8.19-8.16 (m, 1H), 8.12 (dd,J=7.1, 2.3 Hz, 1H), 7.91-7.86 (m, 1H), 7.63-7.58 (m, 1H), 7.35-7.31 (m,1H), 5.77 (s, 2H), 3.78 (s, 3H).

Example 197:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using2-(chloromethyl)pyridine instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₉H₁₃F₃N₄, 354.1; m/z found, 355.3 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.90 (d, J=1.9 Hz, 1H), 8.61-8.58 (m, 1H), 8.51-8.47 (m, 1H), 8.39 (d,J=1.0 Hz, 1H), 8.11-8.04 (m, 2H), 7.74 (td, J=7.7, 1.8 Hz, 1H),7.59-7.53 (m, 1H), 7.31-7.26 (m, 1H), 7.28 (t, J=54.4 Hz, 1H), 7.11-7.06(m, 1H), 5.88 (s, 2H).

Example 198:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 11, StepA, using6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 25) and 3-(chloromethyl)pyridine. MS (ESI): mass calcd.for C₁₉H₁₃F₃N₄, 354.1; m/z found, 355.2 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 8.90 (d, J=1.9 Hz, 1H), 8.74-8.69 (m, 1H), 8.65-8.58 (m, 1H),8.49 (dd, J=4.8, 1.7 Hz, 1H), 8.43-8.38 (m, 1H), 8.14-8.04 (m, 2H),7.72-7.65 (m, 1H), 7.63-7.53 (m, 1H), 7.39-7.32 (m, 1H), 7.30 (t, J=54.2Hz, 1H), 5.81 (s, 2H).

Example 199:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-methyl-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 11,Step A, using6-(3-(difluoromethyl)-4-fluorophenyl)-3-methyl-1H-pyrazolo[4,3-b]pyridine(Intermediate 35) and 3-(chloromethyl)pyridine hydrochloride. MS (ESI):mass calcd. for C₂₀H₁₅F₃N₄, 368.1; m/z found, 369.1 [M+H]⁺. ¹H NMR (400MHz, CDCl₃) δ 8.73 (d, J=1.9 Hz, 1H), 8.64-8.51 (m, 2H), 7.85-7.75 (m,1H), 7.73-7.63 (m, 2H), 7.58-7.47 (m, 1H), 7.34-7.20 (m, 2H), 6.97 (t,J=54.9 Hz, 1H), 5.59 (s, 2H), 2.72 (s, 3H).

Example 200:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using3-(chloromethyl)-5-methylpyridine instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₂₀H₁₅F₃N₄, 368.1; m/z found, 369.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ8.89 (d, J=1.9 Hz, 1H), 8.74-8.63 (m, 1H), 8.45-8.37 (m, 2H), 8.36-8.30(m, 1H), 8.14-8.02 (m, 2H), 7.64-7.53 (m, 1H), 7.53-7.48 (m, 1H), 7.30(t, J=54.1 Hz, 1H), 5.76 (s, 2H), 2.24 (s, 3H).

Example 201:6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 49) and2-(3-(difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₁₉H₁₂F₄N₄, 372.1; m/z found, 373.1 [M+H]⁺.

Example 202:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using3-(chloromethyl)-5-fluoropyridine instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₉H₁₂F₄N₄, 372.1; m/z found, 373.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.91 (d, J=2.1 Hz, 1H), 8.75-8.66 (m, 1H), 8.52 (d, J=2.7 Hz, 1H),8.49-8.45 (m, 1H), 8.42 (s, 1H), 8.15-8.05 (m, 2H), 7.70-7.64 (m, 1H),7.62-7.55 (m, 1H), 7.30 (t, J=54.1 Hz, 1H), 5.85 (s, 2H).

Example 203:5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile

The title compound was made in an analogous manner to Intermediate 25using 5-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)nicotinonitrile(Intermediate 21) and2-(3-(difluoromethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₂₀H₁₂F₃N₅, 379.1; m/z found, 380.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 8.96 (d, J=2.0 Hz, 1H), 8.91 (d, J=1.9 Hz, 1H),8.86 (d, J=2.2 Hz, 1H), 8.73-8.66 (m, 1H), 8.47-8.39 (m, 1H), 8.29-8.21(m, 1H), 8.16-8.03 (m, 2H), 7.65-7.52 (m, 1H), 7.30 (t, J=54.1 Hz, 1H),5.87 (s, 2H).

Example 204:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(6-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using5-(chloromethyl)-2-methoxypyridine instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₂₀H₁₅F₃N₄O, 384.1; m/z found, 385.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ8.88 (d, J=1.9 Hz, 1H), 8.73-8.67 (m, 1H), 8.39-8.33 (m, 1H), 8.29-8.24(m, 1H), 8.14-8.03 (m, 2H), 7.67 (dd, J=8.6, 2.5 Hz, 1H), 7.63-7.53 (m,1H), 7.30 (t, J=54.1 Hz, 1H), 6.76 (d, J=8.6 Hz, 1H), 5.70 (s, 2H), 3.80(s, 3H).

Example 205:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(6-methoxy-2-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using2-(chloromethyl)-6-methoxypyridine instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₂₀H₁₅F₃N₄O, 384.1; m/z found, 385.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ8.91 (d, J=2.0 Hz, 1H), 8.69-8.62 (m, 1H), 8.43-8.33 (m, 1H), 8.13-8.03(m, 2H), 7.67-7.58 (m, 1H), 7.60-7.52 (m, 1H), 7.28 (t, J=54.1 Hz, 1H),6.69 (d, J=8.3 Hz, 1H), 6.62 (d, J=7.3 Hz, 1H), 5.79 (s, 2H), 3.63 (s,3H).

Example 206:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(2-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using3-(chloromethyl)-2-methoxypyridine instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₂₀H₁₅F₃N₄O, 384.1; m/z found, 385.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ8.91 (d, J=1.9 Hz, 1H), 8.65-8.55 (m, 1H), 8.43-8.33 (m, 1H), 8.17-8.01(m, 3H), 7.62-7.51 (m, 1H), 7.29 (t, J=54.1 Hz, 1H), 7.16 (dd, J=7.3,1.9 Hz, 1H), 6.91 (dd, J=7.3, 5.0 Hz, 1H), 5.70 (s, 2H), 3.88 (s, 3H).

Example 207:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using5-(chloromethyl)-3-methoxypyridine instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₂₀H₁₅F₃N₄O, 384.1; m/z found, 385.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.90 (d, J=2.0 Hz, 1H), 8.73-8.69 (m, 1H), 8.43-8.38 (m, 1H), 8.22 (d,J=2.7 Hz, 1H), 8.19-8.14 (m, 1H), 8.13-8.06 (m, 2H), 7.62-7.54 (m, 1H),7.35-7.32 (m, 1H), 7.30 (t, J=54.1 Hz, 1H), 5.79 (s, 2H), 3.78 (s, 3H).

Example 208:1-[(5-Chloro-3-pyridyl)methyl]-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using3-chloro-5-(chloromethyl)pyridine instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₉H₁₂ClF₃N₄, 388.1; m/z found, 389.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆)δ 8.91 (d, J=1.9 Hz, 1H), 8.76-8.67 (m, 1H), 8.59-8.56 (m, 1H), 8.55 (d,J=1.9 Hz, 1H), 8.48-8.38 (m, 1H), 8.17-8.01 (m, 2H), 7.92-7.83 (m, 1H),7.66-7.52 (m, 1H), 7.30 (t, J=54.1 Hz, 1H), 5.83 (s, 2H).

Example 209:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[[5-(difluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using3-(chloromethyl)-5-(difluoromethyl)pyridine (Intermediate 4) instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₂₀H₁₃F₅N₄, 404.1; m/z found, 405.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.91 (d, J=2.0 Hz, 1H), 8.80-8.76 (m, 1H), 8.73 (dd, J=2.0, 1.0 Hz, 1H),8.73-8.69 (m, 1H), 8.43 (d, J=1.0 Hz, 1H), 8.14-8.05 (m, 2H), 7.96-7.89(m, 1H), 7.62-7.55 (m, 1H), 7.30 (t, J=54.1 Hz, 1H), 7.13 (t, J=55.2 Hz,1H), 5.89 (s, 2H).

Example 210:1-[[5-(Difluoromethoxy)-3-pyridyl]methyl]-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 12using 3-(chloromethyl)-5-(difluoromethoxy)pyridine (Intermediate 3)instead of 3-(chloromethyl)pyridine. MS (ESI): mass calcd. forC₂₀H₁₃F₅N₅O, 420.1; m/z found, 421.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.91 (d, J=1.9 Hz, 1H), 8.71 (dd, J=2.0, 1.0 Hz, 1H), 8.49-8.47 (m, 1H),8.44-8.41 (m, 2H), 8.11-8.06 (m, 2H), 7.64-7.61 (m, 1H), 7.61-7.55 (m,1H), 7.30 (t, J=54.1 Hz, 1H), 7.28 (t, J=73.0 Hz, 1H), 5.85 (s, 2H).

Example 211:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[[5-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using(5-(trifluoromethyl)pyridin-3-yl)methyl methanesulfonate (Intermediate10) instead of 2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): masscalcd. for C₂₀H₁₂F₆N₄, 422.1; m/z found, 423.2 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.94-8.90 (m, 2H), 8.88-8.84 (m, 1H), 8.75-8.71 (m, 1H),8.45-8.42 (m, 1H), 8.22-8.18 (m, 1H), 8.12-8.07 (m, 2H), 7.62-7.55 (m,1H), 7.30 (t, J=54.1 Hz, 1H), 5.92 (s, 2H).

Example 212:5-[[6-[3-(Difluoromethyl)-2-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile

The title compound was made in an analogous manner Intermediate 25 using5-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)nicotinonitrile(Intermediate 21) and (3-(difluoromethyl)-2-fluorophenyl)boronic acid.MS (ESI): mass calcd. for C₂₀H₁₂F₃N₅, 379.1; m/z found, 380.1 [M+H]⁺. ¹HNMR (300 MHz, DMSO-d₆) δ 8.96 (d, J=2.0 Hz, 1H), 8.86 (d, J=2.1 Hz, 1H),8.79-8.69 (m, 1H), 8.66-8.58 (m, 1H), 8.46 (s, 1H), 8.31-8.22 (m, 1H),7.96-7.86 (m, 1H), 7.80-7.71 (m, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.32 (t,J=54.2 Hz, 1H), 5.86 (s, 2H).

Example 213:1-[(5-Chloro-3-pyridyl)methyl]-6-[3-(difluoromethyl)-2-fluoro-phenyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using6-bromo-1-((5-chloropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 18) and (3-(difluoromethyl)-2-fluorophenyl)boronic acid.MS (ESI): mass calcd. for C₁₉H₁₂ClF₃N₄, 388.1; m/z found, 389.1 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 8.76-8.69 (m, 1H), 8.67-8.60 (m, 1H), 8.57(d, J=2.4 Hz, 1H), 8.56-8.53 (m, 1H), 8.46 (s, 1H), 7.95-7.83 (m, 2H),7.81-7.70 (m, 1H), 7.54 (t, J=7.8 Hz, 1H), 7.32 (t, J=54.2 Hz, 1H), 5.82(s, 2H).

Example 214:6-(3,4-Dichlorophenyl)-1-[(6-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 49) and (3,4-dichlorophenyl)boronic acid. MS (ESI): masscalcd. for C₁₈H₁₁C₁₂FN₄, 372.0; m/z found, 373.0 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.93 (d, J=1.9 Hz, 1H), 8.78-8.74 (m, 1H), 8.42-8.39 (m,1H), 8.34-8.31 (m, 1H), 8.18 (d, J=2.2 Hz, 1H), 7.93 (td, J=8.2, 2.5 Hz,1H), 7.90-7.87 (m, 1H), 7.83-7.80 (m, 1H), 7.15 (dd, J=8.5, 2.7 Hz, 1H),5.80 (s, 2H).

Example 215:6-(3,4-Dichlorophenyl)-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using6-bromo-1-((5-methoxypyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 14) and (3,4-dichlorophenyl)boronic acid. MS (ESI): masscalcd. for C₁₉H₁₄C₁₂N₄O, 384.0; m/z found, 385.0 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.93 (d, J=1.9 Hz, 1H), 8.74 (dd, J=2.0, 1.0 Hz, 1H),8.41 (d, J=1.0 Hz, 1H), 8.22 (d, J=2.8 Hz, 1H), 8.19-8.15 (m, 2H), 7.88(dd, J=8.4, 2.2 Hz, 1H), 7.81 (d, J=8.4 Hz, 1H), 7.35-7.32 (m, 1H), 5.78(s, 2H), 3.78 (s, 3H).

Example 216:6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 11, StepA, using6-(3-(1,1-difluoroethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 28) and 3-(chloromethyl)pyridine. MS (ESI): mass calcd.for C₂₀H₁₅F₃N₄, 368.1; m/z found, 369.1 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 8.90 (d, J=1.9 Hz, 1H), 8.71-8.66 (m, 1H), 8.63-8.58 (m, 1H),8.49 (dd, J=4.8, 1.6 Hz, 1H), 8.40 (s, 1H), 8.07-7.99 (m, 1H), 8.00-7.93(m, 1H), 7.71-7.64 (m, 1H), 7.56 (dd, J=11.0, 8.6 Hz, 1H), 7.38-7.30 (m,1H), 5.81 (s, 2H), 2.10 (t, J=19.1 Hz, 3H).

Example 217:6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(1,1-difluoroethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 28) and 3-(chloromethyl)-5-methylpyridine. MS (ESI): masscalcd. for C₂₁H₁₇F₃N₄, 382.1; m/z found, 383.2 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 8.90 (d, J=1.9 Hz, 1H), 8.73-8.63 (m, 1H), 8.46-8.37 (m, 2H),8.36-8.29 (m, 1H), 8.10-7.99 (m, 1H), 8.01-7.92 (m, 1H), 7.56 (dd,J=11.2, 8.7 Hz, 1H), 7.54-7.46 (m, 1H), 5.77 (s, 2H), 2.24 (s, 3H), 2.10(t, J=19.2 Hz, 3H).

Example 218:6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(1,1-difluoroethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 28) and 3-(chloromethyl)-5-fluoropyridine. MS (ESI): masscalcd. for C₂₀H₁₄F₄N₄, 386.1; m/z found, 387.1 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 8.91 (d, J=1.9 Hz, 1H), 8.74-8.64 (m, 1H), 8.52 (d, J=2.8 Hz,1H), 8.49-8.43 (m, 1H), 8.42 (s, 1H), 8.10-7.99 (m, 1H), 8.00-7.93 (m,1H), 7.70-7.62 (m, 1H), 7.56 (dd, J=11.0, 8.6 Hz, 1H), 5.85 (s, 2H),2.10 (t, J=19.1 Hz, 3H).

Example 219:5-[[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile

The title compound was made in an analogous manner to Intermediate 25using 5-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)nicotinonitrile(Intermediate 21) and2-(3-(1,1-difluoroethyl)-4-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₂₁H₁₄F₃N₅, 393.1; m/z found, 394.1 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.99-8.94 (m, 1H), 8.94-8.89 (m, 1H), 8.88-8.83(m, 1H), 8.71-8.66 (m, 1H), 8.43 (s, 1H), 8.28-8.23 (m, 1H), 8.08-8.01(m, 1H), 8.00-7.95 (m, 1H), 7.61-7.52 (m, 1H), 5.87 (s, 2H), 2.10 (t,J=19.1 Hz, 3H).

Example 220:6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 11, StepA, using6-(3-(1,1-difluoroethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 28) and 3-(chloromethyl)-5-methoxypyridine. MS (ESI): masscalcd. for C₂₁H₁₇F₃N₄O, 398.1; m/z found, 399.2 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 8.90 (d, J=1.9 Hz, 1H), 8.72-8.65 (m, 1H), 8.41 (s, 1H), 8.22(d, J=2.8 Hz, 1H), 8.17-8.13 (m, 1H), 8.08-8.00 (m, 1H), 8.00-7.92 (m,1H), 7.56 (dd, J=11.0, 8.6 Hz, 1H), 7.37-7.30 (m, 1H), 5.79 (s, 2H),3.78 (s, 3H), 2.10 (t, J=19.1 Hz, 3H).

Example 221:1-[(5-Chloro-3-pyridyl)methyl]-6-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(1,1-difluoroethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 28) and 3-chloro-5-(chloromethyl)pyridine. MS (ESI): masscalcd. for C₂₀H₁₄ClF₃N₄, 402.1; m/z found, 403.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.91 (d, J=2.2 Hz, 1H), 8.72-8.67 (m, 1H), 8.57 (d,J=2.4 Hz, 1H), 8.55-8.52 (m, 1H), 8.42 (s, 1H), 8.07-8.01 (m, 1H),8.01-7.95 (m, 1H), 7.90-7.83 (m, 1H), 7.61-7.52 (m, 1H), 5.83 (s, 2H),2.10 (t, J=19.1 Hz, 3H).

Example 222:6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 2-(chloromethyl)pyridine. MS (ESI): mass calcd.for C₁₉H₁₃F₃N₄O, 370.1; m/z found, 371.2 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.90 (d, J=1.9 Hz, 1H), 8.58-8.53 (m, 1H), 8.51-8.47 (m, 1H),8.41-8.36 (m, 1H), 7.85 (dd, J=7.6, 2.2 Hz, 1H), 7.80-7.71 (m, 2H), 7.58(dd, J=10.5, 8.6 Hz, 1H), 7.37 (t, J=73.2 Hz, 1H), 7.32-7.26 (m, 1H),7.12-7.07 (m, 1H), 5.87 (s, 2H).

Example 223:6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 11, StepA, using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 3-(chloromethyl)pyridine. MS (ESI): mass calcd.for C₁₉H₁₃F₃N₄O, 370.1; m/z found, 371.2 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 8.90 (d, J=1.9 Hz, 1H), 8.69-8.65 (m, 1H), 8.64-8.58 (m, 1H),8.49 (dd, J=4.8, 1.6 Hz, 1H), 8.43-8.37 (m, 1H), 7.87 (dd, J=7.6, 2.2Hz, 1H), 7.83-7.76 (m, 1H), 7.71-7.65 (m, 1H), 7.60 (dd, J=10.4, 8.8 Hz,1H), 7.38 (t, J=73.3 Hz, 1H), 7.37-7.30 (m, 1H), 5.80 (s, 2H).

Example 224:6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 3-(chloromethyl)-5-methylpyridine. MS (ESI): masscalcd. for C₂₀H₁₅F₃N₄O, 384.1; m/z found, 385.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.90 (d, J=2.0 Hz, 1H), 8.66-8.63 (m, 1H), 8.42-8.40 (m, 1H),8.40-8.38 (m, 1H), 8.35-8.31 (m, 1H), 7.86 (dd, J=7.6, 2.3 Hz, 1H),7.82-7.77 (m, 1H), 7.60 (dd, J=10.5, 8.6 Hz, 1H), 7.53-7.50 (m, 1H),7.37 (t, J=73.2 Hz, 1H), 5.75 (s, 2H), 2.24 (s, 3H).

Example 225:6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 3-(chloromethyl)-5-fluoropyridine. MS (ESI): masscalcd. for C₁₉H₁₂F₄N₄O, 388.1; m/z found, 389.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.91 (d, J=2.0 Hz, 1H), 8.68-8.64 (m, 1H), 8.54-8.50 (m, 1H),8.49-8.45 (m, 1H), 8.42 (d, J=1.0 Hz, 1H), 7.87 (dd, J=7.6, 2.3 Hz, 1H),7.83-7.76 (m, 1H), 7.68-7.63 (m, 1H), 7.60 (dd, J=10.5, 8.6 Hz, 1H),7.37 (t, J=73.2 Hz, 1H), 5.84 (s, 2H).

Example 226:5-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile

The title compound was prepared in a manner analogous to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 5-(chloromethyl)pyridine-3-carbonitrile. MS (ESI):mass calcd. for C₂₀H₁₂F₃N₅O, 395.1; m/z found, 396.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.96 (d, J=2.0 Hz, 1H), 8.91 (d, J=1.9 Hz, 1H), 8.86 (d,J=2.2 Hz, 1H), 8.69-8.64 (m, 1H), 8.43 (d, J=1.0 Hz, 1H), 8.28-8.23 (m,1H), 7.87 (dd, J=7.6, 2.3 Hz, 1H), 7.83-7.77 (m, 1H), 7.61 (dd, J=10.5,8.6 Hz, 1H), 7.37 (t, J=73.2 Hz, 1H), 5.86 (s, 2H).

Example 227:6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(6-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 5-(chloromethyl)-2-methoxypyridine. MS (ESI): masscalcd. for C₂₀H₁₅F₃N₄O₂, 400.1; m/z found, 401.1 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 8.89 (d, J=1.9 Hz, 1H), 8.70-8.64 (m, 1H), 8.37 (s, 1H),8.29-8.24 (m, 1H), 7.91-7.83 (m, 1H), 7.83-7.76 (m, 1H), 7.67 (dd,J=8.6, 2.5 Hz, 1H), 7.60 (dd, J=10.5, 8.8 Hz, 1H), 7.38 (t, J=73.2 Hz,1H), 6.76 (d, J=8.5 Hz, 1H), 5.69 (s, 2H), 3.80 (s, 3H).

Example 228:6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(6-methoxy-2-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 2-(chloromethyl)-6-methoxypyridine. MS (ESI): masscalcd. for C₂₀H₁₅F₃N₄O₂, 400.1; m/z found, 401.2 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 8.91 (d, J=1.9 Hz, 1H), 8.65-8.57 (m, 1H), 8.42-8.35 (m,1H), 7.85 (dd, J=7.7, 2.2 Hz, 1H), 7.81-7.74 (m, 1H), 7.67-7.59 (m, 1H),7.57 (dd, J=10.4, 8.6 Hz, 1H), 7.37 (t, J=73.2 Hz, 1H), 6.69 (d, J=8.3Hz, 1H), 6.62 (d, J=7.3 Hz, 1H), 5.78 (s, 2H), 3.63 (s, 3H).

Example 229:6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(2-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 3-(chloromethyl)-2-methoxypyridine. MS (ESI): masscalcd. for C₂₀H₁₅F₃N₄O₂, 400.1; m/z found, 401.2 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.90 (d, J=2.0 Hz, 1H), 8.57-8.53 (m, 1H), 8.38 (d,J=1.0 Hz, 1H), 8.10 (dd, J=5.0, 1.8 Hz, 1H), 7.86 (dd, J=7.6, 2.3 Hz,1H), 7.81-7.76 (m, 1H), 7.59 (dd, J=10.5, 8.6 Hz, 1H), 7.38 (t, J=73.2Hz, 1H), 7.19-7.15 (m, 1H), 6.91 (dd, J=7.3, 5.0 Hz, 1H), 5.69 (s, 2H),3.88 (s, 3H).

Example 230:6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 3-(chloromethyl)-5-methoxypyridine. MS (ESI): masscalcd. for C₂₀H₁₅F₃N₄O₂, 400.1; m/z found, 401.2 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 8.90 (d, J=1.9 Hz, 1H), 8.70-8.62 (m, 1H), 8.40 (s, 1H),8.22 (d, J=2.8 Hz, 1H), 8.18-8.14 (m, 1H), 7.90-7.83 (m, 1H), 7.83-7.75(m, 1H), 7.61 (dd, J=10.7, 8.6 Hz, 1H), 7.38 (t, J=72.8 Hz, 1H),7.36-7.29 (m, 1H), 5.78 (s, 2H), 3.78 (s, 3H).

Example 231:1-[(5-Chloro-3-pyridyl)methyl]-6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 3-chloro-5-(chloromethyl)pyridine. MS (ESI): masscalcd. for C₁₉H₁₂ClF₃N₄O, 404.1; m/z found, 405.1 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 8.96-8.87 (m, 1H), 8.72-8.65 (m, 1H), 8.62-8.50 (m, 2H),8.47-8.38 (m, 1H), 7.93-7.83 (m, 2H), 7.84-7.74 (m, 1H), 7.67-7.55 (m,1H), 7.38 (t, J=73.0 Hz, 1H), 5.82 (s, 2H).

Example 232:6-[4-chloro-3-(Difluoromethyl)phenyl]-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using6-bromo-1-((5-methoxypyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 14) and2-(4-chloro-3-(difluoromethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₂₀H₁₅ClF₂N₄O, 400.1; m/z found, 401.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.92 (d, J=1.9 Hz, 1H), 8.77-8.71 (m, 1H),8.41 (s, 1H), 8.22 (d, J=2.8 Hz, 1H), 8.18-8.15 (m, 1H), 8.15-8.12 (m,1H), 8.08-8.03 (m, 1H), 7.79 (d, J=8.4 Hz, 1H), 7.36-7.32 (m, 1H), 7.30(t, J=54.1 Hz, 1H), 5.80 (s, 2H), 3.78 (s, 3H).

Example 233:1-[(5-Fluoro-3-pyridyl)methyl]-6-[4-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((5-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 54) and (4-fluoro-3-(trifluoromethyl)phenyl)boronic acid.MS (ESI): mass calcd. for C₁₉H₁₁F₅N₄, 390.1; m/z found, 391.1 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.95 (d, J=1.9 Hz, 1H), 8.76-8.74 (m, 1H), 8.52(d, J=2.8 Hz, 1H), 8.48-8.46 (t, J=1.8 Hz, 1H), 8.44-8.42 (d, J=1.1 Hz,1H), 8.26-8.19 (m, 2H), 7.73 (dd, J=10.6, 8.7 Hz, 1H), 7.69-7.65 (m,1H), 5.85 (s, 2H).

Example 234:6-[4-Fluoro-3-(trifluoromethyl)phenyl]-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using6-bromo-1-((5-methoxypyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 14) and (4-fluoro-3-(trifluoromethyl)phenyl)boronic acid.MS (ESI): mass calcd. for C₂₀H₁₄F₄N₄O, 402.1; m/z found, 403.2 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.93 (d, J=2.0 Hz, 1H), 8.74 (dd, J=2.0, 1.0Hz, 1H), 8.41 (d, J=1.0 Hz, 1H), 8.26-8.18 (m, 3H), 8.17 (d, J=1.8 Hz,1H), 7.72 (dd, J=10.7, 8.7 Hz, 1H), 7.34 (dd, J=2.8, 1.8 Hz, 1H), 5.78(s, 2H), 3.78 (s, 3H).

Example 235:6-(3-Bromo-4-fluorophenyl)-1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 49) and (3-bromo-4-fluorophenyl)boronic acid. MS (ESI):mass calcd. for C₁₈H₁₁BrF₂N₄, 401.2; m/z found, 403.1 MS [M+H]⁺.

Example 236:5-[[6-[4-Chloro-3-(1,1-difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile

The title compound was made in an analogous manner to Intermediate 25using 5-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)nicotinonitrile(Intermediate 21) and2-(4-chloro-3-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₂₁H₁₄ClF₂N₅, 409.1; m/z found, 410.1 [M+H]⁺.¹H NMR (500 MHz, DMSO-d₆) δ 8.96 (d, J=2.0 Hz, 1H), 8.93 (d, J=1.9 Hz,1H), 8.86 (d, J=2.2 Hz, 1H), 8.74-8.70 (m, 1H), 8.44 (d, J=1.0 Hz, 1H),8.28-8.23 (m, 1H), 8.04 (d, J=2.2 Hz, 1H), 8.00 (dd, J=8.3, 2.3 Hz, 1H),7.78 (d, J=8.3 Hz, 1H), 5.88 (s, 2H), 2.14 (t, J=19.0 Hz, 3H).

Example 237:6-[4-Chloro-3-(1,1-difluoroethyl)phenyl]-1-[(5-chloro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using6-bromo-1-((5-chloropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 18) and2-(4-chloro-3-(1,1-difluoroethyl)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₂₀H₁₄Cl₂F₂N₄, 418.1; m/z found, 419.1 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 8.93 (d, J=1.9 Hz, 1H), 8.77-8.70 (m, 1H),8.57 (d, J=2.4 Hz, 1H), 8.54 (d, J=1.9 Hz, 1H), 8.44 (s, 1H), 8.08-8.02(m, 1H), 8.03-7.94 (m, 1H), 7.92-7.84 (m, 1H), 7.78 (d, J=8.3 Hz, 1H),5.84 (s, 2H), 2.14 (t, J=19.0 Hz, 3H).

Example 238:6-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 11, StepA, using:6-(4-chloro-3-(difluoromethoxy)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 27) and 3-(chloromethyl)pyridine. MS (ESI): mass calcd.for C₁₉H₁₃ClF₂N₄O, 386.1; m/z found, 387.1 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 8.93 (d, J=1.9 Hz, 1H), 8.73-8.68 (m, 1H), 8.64-8.58 (m, 1H),8.49 (dd, J=4.9, 1.6 Hz, 1H), 8.42 (s, 1H), 7.89-7.81 (m, 1H), 7.81-7.75(m, 2H), 7.72-7.64 (m, 1H), 7.44 (t, J=73.3 Hz, 1H), 7.39-7.30 (m, 1H),5.81 (s, 2H).

Example 239:6-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(4-chloro-3-(difluoromethoxy)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 27) and 3-(chloromethyl)-5-methylpyridine. MS (ESI): masscalcd. for C₂₀H₁₅ClF₂N₄O, 400.1; m/z found, 401.1 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 8.93 (d, J=1.9 Hz, 1H), 8.72-8.66 (m, 1H), 8.44-8.37 (m,2H), 8.36-8.30 (m, 1H), 7.87-7.82 (m, 1H), 7.82-7.75 (m, 2H), 7.55-7.49(m, 1H), 7.44 (t, J=73.2 Hz, 1H), 5.76 (s, 2H), 2.24 (s, 3H).

Example 240:6-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(4-chloro-3-(difluoromethoxy)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 27) and 3-(chloromethyl)-5-fluoropyridine. MS (ESI): masscalcd. for C₁₉H₁₂ClF₃N₄O, 404.1; m/z found, 405.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.94 (d, J=1.9 Hz, 1H), 8.70 (dd, J=2.0, 1.1 Hz, 1H),8.52 (d, J=2.8 Hz, 1H), 8.48-8.45 (m, 1H), 8.43 (d, J=1.0 Hz, 1H),7.87-7.82 (m, 1H), 7.81-7.75 (m, 2H), 7.69-7.62 (m, 1H), 7.43 (t, J=73.2Hz, 1H), 5.85 (s, 2H).

Example 241:5-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile

The title compound was made in an analogous manner to Intermediate 25using 5-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)nicotinonitrile(Intermediate 21) and2-(4-chloro-3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.MS (ESI): mass calcd. for C₂₀H₁₂ClF₂N₅O, 411.1; m/z found, 412.1 [M+H]⁺.¹H NMR (300 MHz, DMSO-d₆) δ 8.97 (d, J=2.0 Hz, 1H), 8.94 (d, J=1.9 Hz,1H), 8.86 (d, J=2.1 Hz, 1H), 8.73-8.68 (m, 1H), 8.44 (s, 1H), 8.29-8.23(m, 1H), 7.89-7.83 (m, 1H), 7.82-7.75 (m, 2H), 7.44 (t, J=73.2 Hz, 1H),5.87 (s, 2H).

Example 242:6-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 11, StepA, using6-(4-chloro-3-(difluoromethoxy)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 27) and 3-(chloromethyl)-5-methoxypyridine. MS (ESI): masscalcd. for C₂₀H₁₅ClF₂N₄O₂, 416.1; m/z found, 417.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.94-8.91 (m, 1H), 8.71-8.68 (m, 1H), 8.41 (s, 1H),8.24-8.20 (m, 1H), 8.18-8.13 (m, 1H), 7.86-7.82 (m, 1H), 7.81-7.75 (m,2H), 7.43 (t, J=73.2 Hz, 1H), 7.35-7.31 (m, 1H), 5.78 (s, 2H), 3.78 (s,3H).

Example 243:6-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(5-chloro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(4-chloro-3-(difluoromethoxy)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 27) and 3-chloro-5-(chloromethyl)pyridine. MS (ESI): masscalcd. for C₁₉H₁₂C₁₂F₂N₄O, 420.0; m/z found, 421.0 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 8.94 (d, J=1.9 Hz, 1H), 8.75-8.67 (m, 1H), 8.57 (d,J=2.4 Hz, 1H), 8.54 (d, J=1.8 Hz, 1H), 8.44 (s, 1H), 7.91-7.82 (m, 2H),7.82-7.75 (m, 2H), 7.44 (t, J=73.2 Hz, 1H), 5.83 (s, 2H).

Example 244:6-(2,4-Difluoro-3-methyl-phenyl)-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate53) and (2,4-difluoro-3-methylphenyl)boronic acid. MS (ESI): mass calcd.for C₁₉H₁₄F₂N₄, 336.1; m/z found, 337.0 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.68 (t, J=1.9 Hz, 1H), 8.50-8.47 (m, 1H), 8.40-8.36 (m, 1H),8.38-8.36 (m, 1H), 7.75 (td, J=7.7, 1.8 Hz, 1H), 7.56-7.50 (m, 1H),7.31-7.27 (m, 1H), 7.27-7.22 (m, 1H), 7.15-7.11 (m, 1H), 5.85 (s, 2H),2.26-2.23 (m, 3H).

Example 245:6-(2,4-Difluoro-3-methyl-phenyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridinetrifluoroacetate Salt

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-(pyridin-3-ylmethyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate50) and using (2,4-difluoro-3-methylphenyl)boronic acid. MS (ESI): masscalcd. for C₁₉H₁₄F₂N₄, 336.1; m/z found, 337.1 [M+H]⁺. ¹H NMR (400 MHz,DMSO-d₆) δ 8.73-8.71 (m, 1H), 8.69 (t, J=2.0 Hz, 1H), 8.62-8.59 (m, 1H),8.53-8.51 (m, 1H), 8.44-8.42 (m, 1H), 7.95-7.90 (m, 1H), 7.60-7.51 (m,2H), 7.30-7.23 (m, 1H), 5.85 (s, 2H), 2.28-2.23 (m, 3H).

Example 246:6-(2,4-Difluoro-3-methyl-phenyl)-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((5-methylpyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 51) and (2,4-difluoro-3-methylphenyl)boronic acid. MS(ESI): mass calcd. for C₂₀H₁₆F₂N₄, 350.1; m/z found, 351.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.67 (t, J=1.9 Hz, 1H), 8.51-8.49 (m, 1H),8.42-8.39 (m, 2H), 8.34-8.32 (m, 1H), 7.60-7.50 (m, 2H), 7.29-7.23 (m,1H), 5.74 (s, 2H), 2.28-2.22 (m, 6H).

Example 247:6-(2,4-Difluoro-3-methyl-phenyl)-1-[(4-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridinetrifluoroacetate Salt

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((4-methylpyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 52) and (2,4-difluoro-3-methylphenyl)boronic acid. MS(ESI): mass calcd. for C₂₀H₁₆F₂N₄, 350.1; m/z found, 351.1 [M+H]⁺. ¹HNMR (400 MHz, DMSO-d₆) δ 8.71 (t, J=1.9 Hz, 1H), 8.60 (d, J=5.5 Hz, 1H),8.52-8.49 (m, 1H), 8.46-8.43 (m, 1H), 8.36 (s, 1H), 7.67 (d, J=5.5 Hz,1H), 7.60-7.52 (m, 1H), 7.30-7.24 (m, 1H), 5.90 (s, 2H), 2.27-2.24 (m,3H).

Example 248:6-(2,4-Difluoro-3-methyl-phenyl)-1-[(6-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 49) and (2,4-difluoro-3-methylphenyl)boronic acid. MS(ESI): mass calcd. for C₁₉H₁₃F₃N₄, 354.1; m/z found, 355.1 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.68 (t, J=1.9 Hz, 1H), 8.54-8.52 (m, 1H),8.42-8.40 (m, 1H), 8.32-8.30 (m, 1H), 7.91 (td, J=8.2, 2.5 Hz, 1H),7.59-7.53 (m, 1H), 7.29-7.23 (m, 1H), 7.14 (dd, J=8.5, 2.6 Hz, 1H), 5.79(s, 2H), 2.27-2.24 (m, 3H).

Example 249:6-(2,4-Difluoro-3-methyl-phenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridinetrifluoroacetate Salt

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((5-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 54) and (2,4-difluoro-3-methylphenyl)boronic acid. MS(ESI): mass calcd. for C₁₉H₁₃F₃N₄, 354.1; m/z found, 355.1 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 8.69 (t, J=1.9 Hz, 1H), 8.55-8.51 (m, 2H),8.48-8.45 (m, 1H), 8.44-8.42 (m, 1H), 7.69-7.64 (m, 1H), 7.60-7.53 (m,1H), 7.29-7.23 (m, 1H), 5.83 (s, 2H), 2.27-2.24 (m, 3H).

Example 250:1-(2-Pyridylmethyl)-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate53) and (3,4,5-trifluorophenyl)boronic acid. MS (ESI): mass calcd. forC₁₈H₁₁F₃N₄, 340.1; m/z found, 341.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.95 (d, J=2.0 Hz, 1H), 8.67-8.65 (m, 1H), 8.50-8.47 (m, 1H), 8.41-8.39(m, 1H), 7.95-7.88 (m, 2H), 7.75 (td, J=7.7, 1.8 Hz, 1H), 7.31-7.27 (m,1H), 7.10-7.07 (m, 1H), 5.86 (s, 2H).

Example 251:1-[(5-Fluoro-3-pyridyl)methyl]-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-((5-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 54) and (3,4,5-trifluorophenyl)boronic acid. MS (ESI):mass calcd. for C₁₈H₁₀F₄N₄, 358.1; m/z found, 359.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.96 (d, J=1.9 Hz, 1H), 8.76-8.74 (dd, J=2.0, 1.0 Hz,1H), 8.52 (d, J=2.8 Hz, 1H), 8.49 (t, J=1.8 Hz, 1H), 8.43 (d, J=0.9 Hz,1H), 7.98-7.90 (m, 2H), 7.70-7.66 (m, 1H), 5.83 (s, 2H).

Example 252:1-[(5-Methoxy-3-pyridyl)methyl]-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using6-bromo-1-((5-methoxypyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 14) and (3,4,5-trifluorophenyl)boronic acid. MS (ESI):mass calcd. for C₁₉H₁₃F₃N₄O, 370.1; m/z found, 371.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.94 (d, J=2.0 Hz, 1H), 8.76-8.72 (m, 1H), 8.44-8.38 (m,1H), 8.22 (d, J=2.8 Hz, 1H), 8.18 (d, J=1.7 Hz, 1H), 7.98-7.88 (m, 2H),7.37-7.30 (m, 1H), 5.76 (s, 2H), 3.78 (s, 3H).

Example 253:1-[[5-(Difluoromethoxy)-3-pyridyl]methyl]-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Intermediate 25using6-bromo-1-((5-(difluoromethoxy)pyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 17) and (3,4,5-trifluorophenyl)boronic acid. MS (ESI):mass calcd. for C₁₉H₁₁F₅N₄O, 406.1; m/z found, 407.1 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 8.96 (d, J=1.9 Hz, 1H), 8.80-8.71 (m, 1H), 8.52-8.46 (m,1H), 8.46-8.38 (m, 2H), 8.01-7.86 (m, 2H), 7.69-7.61 (m, 1H), 7.29 (t,J=73.2 Hz, 1H), 5.82 (s, 2H).

Example 254:1-(Pyridazin-4-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 1,using pyridazin-4-ylmethyl methanesulfonate (Intermediate 8) instead of2-(chloromethyl)pyrimidine hydrochloride. MS (ESI): mass calcd. forC₁₈H₁₂F₃N₅, 355.1; m/z found, 356.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ9.19-9.17 (m, 1H), 9.16-9.13 (m, 1H), 8.99 (d, J=1.9 Hz, 1H), 8.75-8.72(m, 1H), 8.51-8.46 (m, 1H), 8.20-8.13 (m, 2H), 7.85-7.76 (m, 2H),7.39-7.34 (m, 1H), 5.91 (s, 2H).

Example 255: 6-(m-Tolyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-(pyridazin-3-ylmethyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 48) and m-tolylboronic acid. MS (ESI): mass calcd. forC₁₈H₁₅N₅, 301.1; m/z found, 302.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ9.16 (dd, J=4.9, 1.6 Hz, 1H), 8.90 (d, J=1.9 Hz, 1H), 8.57-8.54 (m, 1H),8.41-8.38 (m, 1H), 7.68-7.64 (m, 2H), 7.64-7.59 (m, 1H), 7.46-7.40 (m,2H), 7.30-7.25 (m, 1H), 6.10 (s, 2H), 2.42 (s, 3H).

Example 256:6-(3-Fluorophenyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridinetrifluoroacetate Salt

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-(pyridazin-3-ylmethyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 48) and (3-fluorophenyl)boronic acid. MS (ESI): masscalcd. for C₁₇H₁₂FN₅, 305.1; m/z found, 306.0 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 9.17 (dd, J=4.9, 1.6 Hz, 1H), 8.96 (d, J=1.9 Hz, 1H),8.68-8.66 (m, 1H), 8.43-8.41 (m, 1H), 7.76-7.69 (m, 2H), 7.67 (dd,J=8.5, 4.9 Hz, 1H), 7.62-7.56 (m, 1H), 7.46 (dd, J=8.5, 1.6 Hz, 1H),7.32-7.27 (m, 1H), 6.10 (s, 2H).

Example 257:6-[3-(1,1-Difluoroethyl)phenyl]-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(1,1-difluoroethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine (Intermediate29) and 3-(chloromethyl)pyridazine. MS (ESI): mass calcd. forC₁₉H₁₅F₂N₅, 351.1; m/z found, 352.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ9.16 (dd, J=4.9, 1.6 Hz, 1H), 8.96 (d, J=1.9 Hz, 1H), 8.71-8.64 (m, 1H),8.43 (s, 1H), 8.03-7.91 (m, 2H), 7.73-7.60 (m, 3H), 7.44 (dd, J=8.5, 1.6Hz, 1H), 6.12 (s, 2H), 2.06 (t, J=18.9 Hz, 3H).

Example 258:1-(Pyridazin-3-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-(pyridazin-3-ylmethyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 48) and (3-(trifluoromethyl)phenyl)boronic acid. MS (ESI):mass calcd. for C₁₈H₁₂F₃N₅, 355.1; m/z found, 356.0 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆) δ 9.16 (dd, J=5.0, 1.6 Hz, 1H), 8.98 (d, J=1.9 Hz, 1H),8.75-8.73 (m, 1H), 8.44-8.43 (m, 1H), 8.20-8.15 (m, 2H), 7.84-7.76 (m,2H), 7.66 (dd, J=8.5, 4.9 Hz, 1H), 7.44 (dd, J=8.5, 1.6 Hz, 1H), 6.12(s, 2H).

Example 259:6-(4-Fluoro-3-methyl-phenyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridinetrifluoroacetate Salt

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-(pyridazin-3-ylmethyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 48) and (4-fluoro-3-methylphenyl)boronic acid. MS (ESI):mass calcd. for C₁₈H₁₄FN₅, 319.1; m/z found, 320.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 9.16 (dd, J=5.0, 1.6 Hz, 1H), 8.89 (d, J=1.9 Hz, 1H),8.58-8.55 (m, 1H), 8.41-8.38 (m, 1H), 7.80-7.77 (m, 1H), 7.71-7.65 (m,2H), 7.45 (dd, J=8.5, 1.6 Hz, 1H), 7.33-7.28 (m, 1H), 6.09 (s, 2H),2.35-2.32 (m, 3H).

Example 260:6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(1,1-difluoroethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 28) and 3-(chloromethyl)pyridazine. MS (ESI): mass calcd.for C₁₉H₁₄F₃N₅, 369.1; m/z found, 370.1 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 9.16 (dd, J=4.9, 1.6 Hz, 1H), 8.93 (d, J=1.9 Hz, 1H),8.69-8.62 (m, 1H), 8.47-8.37 (m, 1H), 8.08-7.99 (m, 1H), 8.01-7.93 (m,1H), 7.66 (dd, J=8.5, 4.9 Hz, 1H), 7.55 (dd, J=11.0, 8.6 Hz, 1H), 7.44(dd, J=8.6, 1.6 Hz, 1H), 6.11 (s, 2H), 2.09 (t, J=19.1 Hz, 3H).

Example 261:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using3-(chloromethyl)pyridazine instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₈H₁₂F₃N₅, 355.1; m/z found, 356.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ9.20-9.13 (m, 1H), 8.93 (d, J=1.9 Hz, 1H), 8.70-8.64 (m, 1H), 8.42 (s,1H), 8.15-8.03 (m, 2H), 7.66 (dd, J=8.5, 4.9 Hz, 1H), 7.62-7.51 (m, 1H),7.44 (dd, J=8.6, 1.6 Hz, 1H), 7.29 (t, J=54.1 Hz, 1H), 6.10 (s, 2H).

Example 262:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(6-methylpyridazin-3-yl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using3-(chloromethyl)-6-methylpyridazine (Intermediate 2) instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₉H₁₄F₃N₅, 369.1; m/z found, 370.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.91 (d, J=2.0 Hz, 1H), 8.66-8.62 (m, 1H), 8.40 (d, J=0.9 Hz, 1H),8.11-8.04 (m, 2H), 7.60-7.54 (m, 1H), 7.51 (d, J=8.6 Hz, 1H), 7.35 (d,J=8.6 Hz, 1H), 7.29 (t, J=54.2 Hz, 1H), 6.05 (s, 2H), 2.57 (s, 3H).

Example 263:6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 12using 6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 3-(chloromethyl)pyridazine. MS (ESI): mass calcd.for C₁₈H₁₂F₃N₅O, 371.1; m/z found, 372.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 9.19-9.14 (m, 1H), 8.92 (d, J=2.0 Hz, 1H), 8.65-8.60 (m, 1H),8.44-8.40 (m, 1H), 7.86 (dd, J=7.5, 2.2 Hz, 1H), 7.81-7.75 (m, 1H), 7.66(dd, J=8.5, 4.9 Hz, 1H), 7.59 (dd, J=10.5, 8.6 Hz, 1H), 7.47-7.43 (m,1H), 7.37 (t, J=73.2 Hz, 1H), 6.09 (s, 2H).

Example 264:6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(6-methylpyridazin-3-yl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 3-(chloromethyl)-6-methylpyridazine (Intermediate2). MS (ESI): mass calcd. for C₁₉H₁₄F₃N₅O, 385.1; m/z found, 386.1[M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ 8.92 (d, J=1.9 Hz, 1H), 8.65-8.56(m, 1H), 8.44-8.36 (m, 1H), 7.91-7.82 (m, 1H), 7.82-7.73 (m, 1H), 7.61(dd, J=8.7, 1.9 Hz, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.38 (t, J=73.2 Hz,1H), 7.35 (d, J=8.6 Hz, 1H), 6.04 (s, 2H), 2.57 (s, 3H).

Example 265:6-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(4-chloro-3-(difluoromethoxy)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 27) and 3-(chloromethyl)pyridazine. MS (ESI): mass calcd.for C₁₈H₁₂ClF₂N₅O, 387.1; m/z found, 388.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 9.19-9.12 (m, 1H), 8.95 (d, J=2.0 Hz, 1H), 8.69-8.64 (m, 1H),8.45-8.42 (m, 1H), 7.86-7.81 (m, 1H), 7.80-7.74 (m, 2H), 7.67 (dd,J=8.5, 5.0 Hz, 1H), 7.47-7.45 (m, 1H), 7.44 (t, J=73.8 Hz, 1H), 6.10 (s,2H).

Example 266:6-(3,4-Difluorophenyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-(pyridazin-3-ylmethyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 48) and (3,4-difluorophenyl)boronic acid. MS (ESI): masscalcd. for C₁₇H₁₁F₂N₅, 323.1; m/z found, 324.0 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 9.17 (dd, J=4.9, 1.6 Hz, 1H), 8.94 (d, J=1.9 Hz, 1H),8.67-8.65 (m, 1H), 8.42 (d, J=1.0 Hz, 1H), 8.00 (ddd, J=12.2, 7.7, 2.3Hz, 1H), 7.75-7.71 (m, 1H), 7.67 (dd, J=8.5, 4.9 Hz, 1H), 7.65-7.59 (m,1H), 7.46 (dd, J=8.5, 1.6 Hz, 1H), 6.09 (s, 2H).

Example 267:6-(4-Chloro-3-methyl-phenyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-(pyridazin-3-ylmethyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 48) and (4-chloro-3-methylphenyl)boronic acid. MS (ESI):mass calcd. for C₁₈H₁₄ClN₅, 335.1; m/z found, 336.0 [M+H]⁺. ¹H NMR (600MHz, DMSO-d₆) δ 9.16 (dd, J=4.9, 1.6 Hz, 1H), 8.91 (d, J=1.9 Hz, 1H),8.62-8.59 (m, 1H), 8.41-8.40 (m, 1H), 7.88-7.85 (m, 1H), 7.71-7.64 (m,2H), 7.59-7.56 (m, 1H), 7.46-7.42 (m, 1H), 6.09 (s, 2H), 2.44 (s, 3H).

Example 268:1-(Pyridazin-3-ylmethyl)-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-(pyridazin-3-ylmethyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 48) and (3,4,5-trifluorophenyl)boronic. MS (ESI): masscalcd. for C₁₇H₁₀F₃N₅, 341.1; m/z found, 342.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 9.17 (dd, J=4.9, 1.6 Hz, 1H), 8.97 (d, J=1.9 Hz, 1H),8.73-8.70 (m, 1H), 8.43 (d, J=1.0 Hz, 1H), 7.96-7.88 (m, 2H), 7.67 (dd,J=8.5, 4.9 Hz, 1H), 7.45 (dd, J=8.6, 1.6 Hz, 1H), 6.08 (s, 2H).

Example 269:6-(2,4-Difluoro-3-methyl-phenyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridinetrifluoroacetate Salt

The title compound was prepared in a manner analogous to Example 4 using6-bromo-1-(pyridazin-3-ylmethyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 48) and (2,4-difluoro-3-methylphenyl)boronic acid. MS(ESI): mass calcd. for C₁₈H₁₃F₂N₅, 337.1; m/z found, 338.0 [M+H]⁺. ¹HNMR (500 MHz, DMSO-d₆) δ 9.17 (dd, J=4.9, 1.6 Hz, 1H), 8.71 (t, J=1.9Hz, 1H), 8.46-8.44 (m, 1H), 8.44-8.42 (m, 1H), 7.67 (dd, J=8.5, 4.9 Hz,1H), 7.58-7.52 (m, 1H), 7.48 (dd, J=8.5, 1.6 Hz, 1H), 7.28-7.22 (m, 1H),6.08 (s, 2H), 2.26-2.24 (m, 3H).

Example 270:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(pyrimidin-4-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using4-(chloromethyl)pyrimidine instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₈H₁₂F₃N₅, 355.1; m/z found, 356.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ9.12-9.07 (m, 1H), 8.93 (d, J=2.0 Hz, 1H), 8.76-8.71 (m, 1H), 8.65-8.60(m, 1H), 8.47-8.42 (m, 1H), 8.11-8.04 (m, 2H), 7.61-7.52 (m, 1H), 7.28(t, J=54.1 Hz, 1H), 7.14-7.10 (m, 1H), 5.94 (s, 2H).

Example 271:6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(pyrimidin-4-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 4-(chloromethyl)pyrimidine. MS (ESI): mass calcd.for C₁₈H₁₂F₃N₅O, 371.1; m/z found, 372.2 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 9.14-9.06 (m, 1H), 8.96-8.90 (m, 1H), 8.73 (dd, J=5.2, 1.7Hz, 1H), 8.61-8.55 (m, 1H), 8.48-8.41 (m, 1H), 7.89-7.81 (m, 1H),7.81-7.73 (m, 1H), 7.63-7.52 (m, 1H), 7.37 (t, J=73.3 Hz, 1H), 7.17-7.08(m, 1H), 5.93 (s, 2H).

Example 272:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(pyrazin-2-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using2-(chloromethyl)pyrazine instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₈H₁₂F₃N₅, 355.1; m/z found, 356.2 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.91 (d, J=1.9 Hz, 1H), 8.66-8.63 (m, 1H), 8.59 (d, J=1.5 Hz, 1H),8.59-8.56 (m, 1H), 8.56-8.54 (m, 1H), 8.39 (d, J=1.0 Hz, 1H), 8.11-8.05(m, 2H), 7.61-7.54 (m, 1H), 7.29 (t, J=54.1 Hz, 1H), 5.97 (s, 2H).

Example 273:6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(pyrazin-2-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 2-(chloromethyl)pyrazine. MS (ESI): mass calcd.for C₁₈H₁₂F₃N₅O, 371.1; m/z found, 372.1 [M+H]⁺. ¹H NMR (500 MHz,DMSO-d₆) δ 8.97-8.86 (m, 1H), 8.65-8.58 (m, 2H), 8.60-8.51 (m, 2H),8.44-8.36 (m, 1H), 7.91-7.82 (m, 1H), 7.83-7.74 (m, 1H), 7.66-7.56 (m,1H), 7.38 (t, J=73.2 Hz, 1H), 5.96 (s, 2H).

Example 274:6-[3-(1,1-Difluoroethyl)phenyl]-1-(pyrimidin-5-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 12using 6-(3-(1,1-difluoroethyl)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 29) and 5-(chloromethyl)pyrimidine. MS (ESI): mass calcd.for C₁₉H₁₅F₂N₅, 351.1; m/z found, 352.1 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 9.13 (s, 1H), 8.98-8.91 (m, 1H), 8.82 (s, 2H), 8.77-8.70 (m,1H), 8.46-8.40 (m, 1H), 8.05-7.93 (m, 2H), 7.74-7.62 (m, 2H), 5.85 (s,2H), 2.07 (t, J=18.9 Hz, 3H).

Example 275:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(pyrimidin-5-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using5-(chloromethyl)pyrimidine instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₈H₁₂F₃N₅, 355.1; m/z found, 356.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ9.13 (s, 1H), 8.91 (d, J=1.9 Hz, 1H), 8.82 (s, 2H), 8.76-8.70 (m, 1H),8.43 (s, 1H), 8.15-8.05 (m, 2H), 7.64-7.54 (m, 1H), 7.31 (t, J=54.1 Hz,1H), 5.84 (s, 2H).

Example 276:1-(Pyrimidin-5-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridinehydrochloride Salt

The title compound was prepared in a manner analogous to Example 6,using 5-pyrimidinemethanol instead of 4-(hydroxymethyl)pyrimidine. ¹HNMR (500 MHz, DMSO-d₆) δ 9.14 (s, 1H), 9.00 (d, J=1.73 Hz, 1H),8.92-8.79 (m, 3H), 8.46 (s, 1H), 8.28-8.15 (m, 2H), 7.74-7.90-7.74 (m,2H), 5.87 (s, 2H).

Example 277:6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-(pyrimidin-5-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 12using6-(3-(1,1-difluoroethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 28) and 5-(chloromethyl)pyrimidine. MS (ESI): mass calcd.for C₁₉H₁₄F₃N₅, 369.1; m/z found, 370.1 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 9.13 (s, 1H), 8.91 (d, J=1.9 Hz, 1H), 8.82 (s, 2H), 8.75-8.68(m, 1H), 8.45-8.39 (m, 1H), 8.09-8.01 (m, 1H), 8.02-7.95 (m, 1H), 7.57(dd, J=11.0, 8.6 Hz, 1H), 5.84 (s, 2H), 2.10 (t, J=19.1 Hz, 3H).

Example 278:6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(pyrimidin-5-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 12using 6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 5-(chloromethyl)pyrimidine. MS (ESI): mass calcd.for C₁₈H₁₂F₃N₅O, 371.1; m/z found, 372.1 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 9.13 (s, 1H), 8.91 (d, J=1.9 Hz, 1H), 8.82 (s, 2H), 8.72-8.66(m, 1H), 8.44-8.39 (m, 1H), 7.92-7.85 (m, 1H), 7.84-7.75 (m, 1H), 7.58(dd, J=10.4, 8.7 Hz, 1H), 7.38 (t, J=73.2 Hz, 1H), 5.83 (s, 2H).

Example 279:6-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(pyrimidin-5-ylmethyl)pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 12using 6-(4-chloro-3-(difluoromethoxy)phenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 27) and 5-(chloromethyl)pyrimidine. MS (ESI): mass calcd.for C₁₈H₁₂ClF₂N₅O, 387.1; m/z found, 388.1 [M+H]⁺. ¹H NMR (300 MHz,DMSO-d₆) δ 9.13 (s, 1H), 8.94 (d, J=1.9 Hz, 1H), 8.82 (s, 2H), 8.77-8.69(m, 1H), 8.47-8.40 (m, 1H), 7.89-7.83 (m, 1H), 7.82-7.76 (m, 2H), 7.44(t, J=73.2 Hz, 1H), 5.84 (s, 2H).

Example 280:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(6-methylpyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using4-(chloromethyl)-6-methylpyrimidine instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₉H₁₄F₃N₅, 369.1; m/z found, 370.1 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ8.99-8.88 (m, 2H), 8.64-8.58 (m, 1H), 8.47-8.40 (m, 1H), 8.13-8.03 (m,2H), 7.62-7.52 (m, 1H), 7.29 (t, J=54.1 Hz, 1H), 7.04-6.98 (m, 1H), 5.87(s, 2H), 2.39 (s, 3H).

Example 281:6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(6-methylpyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 4-(chloromethyl)-6-methylpyrimidine. MS (ESI):mass calcd. for C₁₉H₁₄F₃N₅O, 385.1; m/z found, 386.1 [M+H]⁺. ¹H NMR (500MHz, DMSO-d₆) δ 8.95-8.93 (m, 1H), 8.93-8.92 (m, 1H), 8.59-8.55 (m, 1H),8.43 (d, J=1.0 Hz, 1H), 7.85 (dd, J=7.6, 2.3 Hz, 1H), 7.81-7.75 (m, 1H),7.58 (dd, J=10.5, 8.6 Hz, 1H), 7.36 (t, J=73.2 Hz, 1H), 7.05-6.99 (m,1H), 5.86 (s, 2H), 2.40 (s, 3H).

Example 282:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(2-methylpyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using4-(chloromethyl)-2-methylpyrimidine instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₉H₁₄F₃N₅, 369.1; m/z found, 370.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ8.94 (d, J=1.9 Hz, 1H), 8.65-8.61 (m, 1H), 8.58 (d, J=5.2 Hz, 1H),8.48-8.43 (m, 1H), 8.13-8.03 (m, 2H), 7.62-7.51 (m, 1H), 7.28 (t, J=54.1Hz, 1H), 6.71 (d, J=5.2 Hz, 1H), 5.87 (s, 2H), 2.58 (s, 3H).

Example 283:1-[(2-Methylpyrimidin-4-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 6,using (2-methylpyrimidin-4-yl)methanol instead of4-(hydroxymethyl)pyrimidine. MS (ESI): mass calcd. for C₁₉H₁₄F₃N₅,369.1; m/z found, 370.1 [M+H]⁺.

Example 284:6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(2-methylpyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 4-(chloromethyl)-2-methylpyrimidine. MS (ESI):mass calcd. for C₁₉H₁₄F₃N₅O, 385.1; m/z found, 386.1 [M+H]⁺. ¹H NMR (300MHz, DMSO-d₆) δ 8.94 (d, J=1.9 Hz, 1H), 8.63-8.53 (m, 2H), 8.50-8.39 (m,1H), 7.89-7.82 (m, 1H), 7.82-7.74 (m, 1H), 7.58 (dd, J=10.1, 9.0 Hz,1H), 7.36 (t, J=73.2 Hz, 1H), 6.71 (d, J=5.2 Hz, 1H), 5.86 (s, 2H), 2.58(s, 3H).

Example 285:6-(3,4-Difluorophenyl)-1-[(2-methylpyrimidin-5-yl)methyl]pyrazolo[4,3-b]pyridinetrifluoroacetate Salt

The title compound was prepared in a manner analogous to Example 4 using(3,4-difluorophenyl)boronic acid instead of(3-(trifluoromethyl)phenyl)boronic acid. MS (ESI): mass calcd. forC₁₈H₁₃F₂N₅, 337.1; m/z found, 338.0 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.92 (d, J=1.9 Hz, 1H), 8.75-8.69 (m, 3H), 8.42-8.38 (m, 1H), 8.05-7.99(m, 1H), 7.78-7.72 (m, 1H), 7.68-7.60 (m, 1H), 5.76 (s, 2H), 2.58 (s,3H).

Example 286:6-(4-Chloro-3-methyl-phenyl)-1-[(2-methylpyrimidin-5-yl)methyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 4 using(4-chloro-3-methylphenyl)boronic acid instead of(3-(trifluoromethyl)phenyl)boronic acid. MS (ESI): mass calcd. forC₁₉H₁₆ClN₅, 349.1; m/z found, 350.1 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.89 (d, J=1.9 Hz, 1H), 8.72 (s, 2H), 8.68-8.66 (m, 1H), 8.39-8.38 (m,1H), 7.89-7.86 (m, 1H), 7.73-7.69 (dd, J=8.4, 2.3 Hz, 1H), 7.61-7.56 (m,1H), 5.77 (s, 2H), 2.57 (s, 3H), 2.45 (s, 3H).

Example 287:1-[(5-Methylpyrimidin-2-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine

The title compound was prepared in a manner analogous to Example 1,using 2-(chloromethyl)-5-methylpyrimidine instead of2-(chloromethyl)pyrimidine hydrochloride. MS (ESI): mass calcd. forC₁₉H₁₄F₃N₅, 369.1; m/z found, 370.2 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d₆) δ8.96 (d, J=1.9 Hz, 1H), 8.64-8.62 (m, 1H), 8.58-8.55 (m, 2H), 8.38-8.35(m, 1H), 8.18-8.13 (m, 2H), 7.84-7.74 (m, 2H), 5.97 (s, 2H), 2.22 (s,3H).

Example 288:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(6-methoxypyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using4-(chloromethyl)-6-methoxypyrimidine instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₉H₁₄F₃N₅O, 385.1; m/z found, 386.1 [M+H]⁺. ¹H NMR (500 MHz, DMSO-d₆) δ8.92 (d, J=1.9 Hz, 1H), 8.70 (d, J=1.1 Hz, 1H), 8.63-8.59 (m, 1H), 8.42(d, J=1.0 Hz, 1H), 8.12-8.04 (m, 2H), 7.60-7.53 (m, 1H), 7.28 (t, J=54.1Hz, 1H), 6.51-6.49 (m, 1H), 5.83 (s, 2H), 3.88 (s, 3H).

Example 289:6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(6-methoxypyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 4-(chloromethyl)-6-methoxypyrimidine. MS (ESI):mass calcd. for C₁₉H₁₄F₃N₅O₂, 401.1; m/z found, 402.2 [M+H]⁺. ¹H NMR(500 MHz, DMSO-d₆) δ 8.92 (d, J=2.0 Hz, 1H), 8.70 (d, J=1.1 Hz, 1H),8.59-8.54 (m, 1H), 8.42 (d, J=1.0 Hz, 1H), 7.85 (dd, J=7.6, 2.3 Hz, 1H),7.80-7.75 (m, 1H), 7.58 (dd, J=10.5, 8.6 Hz, 1H), 7.37 (t, J=73.2 Hz,1H), 6.52-6.49 (m, 1H), 5.82 (s, 2H), 3.88 (s, 3H).

Example 290:6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(2-methoxypyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using4-(chloromethyl)-2-methoxypyrimidine instead of2-(chloromethyl)-5-methyl-1,3-oxazole. MS (ESI): mass calcd. forC₁₉H₁₄F₃N₅O, 385.1; m/z found, 386.2 [M+H]⁺. ¹H NMR (300 MHz, DMSO-d₆) δ8.93 (d, J=1.9 Hz, 1H), 8.65-8.59 (m, 1H), 8.51 (d, J=5.0 Hz, 1H),8.47-8.40 (m, 1H), 8.12-8.03 (m, 2H), 7.61-7.51 (m, 1H), 7.28 (t, J=54.1Hz, 1H), 6.66 (d, J=5.0 Hz, 1H), 5.86 (s, 2H), 3.79 (s, 3H).

Example 291:6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(2-methoxypyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine

The title compound was made in an analogous manner to Example 8 using6-(3-(difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 26) and 4-(chloromethyl)-2-methoxypyrimidine. MS (ESI):mass calcd. for C₁₉H₁₄F₃N₅O₂, 401.1; m/z found, 402.1 [M+H]⁺. ¹H NMR(300 MHz, DMSO-d₆) δ 8.93 (d, J=1.9 Hz, 1H), 8.61-8.55 (m, 1H), 8.51 (d,J=5.0 Hz, 1H), 8.46-8.42 (m, 1H), 7.88-7.81 (m, 1H), 7.81-7.74 (m, 1H),7.59 (dd, J=10.2, 8.7 Hz, 1H), 7.36 (t, J=73.2 Hz, 1H), 6.66 (d, J=5.0Hz, 1H), 5.85 (s, 2H), 3.79 (s, 3H).

Example 292:(5-((6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)methanol

Step A.2-(((tert-Butyldimethylsilyl)oxy)methyl)-5-((6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-1,3,4-oxadiazole:6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 65, 187 mg, 0.709 mmol),2-(((tert-butyldimethylsilyl)oxy)methyl)-5-(chloromethyl)-1,3,4-oxadiazole(205 mg, 0.780 mmol), and cesium carbonate (347 mg, 1.06 mmol) weretaken up in DMF (3 mL) and stirred at r.t. for one hour. The reactionmixture was partitioned between water and ethyl acetate, the organiclayer was washed 2× with water, dried (MgSO₄) and concentrated.Purification (FCC, SiO₂, 0-100% ethyl acetate/hexanes) afforded 310 mg(0.633 mmol, 89% yield) of the titled product. MS (ESI): mass calcd. forC₂₃H₂₆F₃N₅O₂Si, 489.2; m/z found, 490.2 [M+H]⁺.

Step B.(5-((6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)methanol:2-(((tert-Butyldimethylsilyl)oxy)methyl)-5-((6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-1,3,4-oxadiazole(263 mg, 0.537 mmol) and cesium fluoride (816 mg, 5.37 mmol) were takenup in MeCN (10 mL) and stirred overnight at r.t. The reaction mixturewas diluted with methanol, concentrated onto Celite®, and purified onsilica gel (50-100% ethyl acetate/hexanes) followed by reverse phaseHPLC (METHOD F) to obtain 66.7 mg (0.178 mmol, 33% yield) of the desiredproduct. MS (ESI): mass calcd. for C₁₇H₁₂F₃N₅O₂, 375.1; m/z found, 376.1[M+H]⁺. ¹H NMR (400 MHz, MeOH-d₄) δ 8.86 (d, J=1.9 Hz, 1H), 8.48 (dd,J=1.9, 1.0 Hz, 1H), 8.31 (d, J=1.0 Hz, 1H), 8.06-7.92 (m, 2H), 7.50-7.39(m, 1H), 7.08 (t, J=54.6 Hz, 1H), 6.07 (s, 2H), 4.69 (s, 2H).

Example 293:2-Fluoro-5-(1-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)benzoicAcid

Step A. Ethyl2-fluoro-5-(1-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)benzoate:To a solution of2-((6-bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole(Intermediate 19, 120 mg, 0.408 mmol) in dioxane (5 mL) were added3-ethoxycarbonyl-4-fluorophenylboronic acid (115 mg, 0.530 mmol), RuPhosPd G3 (17 mg, 0.020 mmol), and cesium carbonate (399 mg, 1.22 mmol). Thereaction mixture was stirred at 100° C. overnight, allowed to cool tor.t., and partitioned between water and DCM. The aqueous layer wasextracted 2× with DCM and the combined organic layers were concentratedand purified on silica gel (0-100% ethyl acetate/hexanes) to obtain 70mg (0.184 mmol, 45% yield) of the desired product. MS (ESI): mass calcd.for C₁₉H₁₆FN₅O₃, 381.1; m/z found, 382.2 [M+H]⁺.

Step B.2-Fluoro-5-(1-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-6-ylbenzoicacid: Ethyl2-fluoro-5-(1-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)benzoate(70 mg, 0.184 mmol) was dissolved in MeOH (1 mL) and 1N aq. NaOHsolution (1 mL) was added. The mixture was stirred at room temperaturefor one hour, acidified carefully with 1N aq. HCl, and extracted 5× withDCM. The combined organics were concentrated and purified by reversephase HPLC (METHOD G) to obtain 2.5 mg (0.0071 mmol, 4% yield) of thetitle compound. MS (ESI): mass calcd. for C₁₇H₁₂FN₅O₃, 353.1; m/z found,354.1 [M+H]⁺. ¹H NMR (400 MHz, chloroform-d) δ 8.80 (d, J=1.9 Hz, 1H),8.31 (d, J=1.0 Hz, 1H), 8.24 (dd, J=6.7, 2.6 Hz, 1H), 8.02 (s, 1H),7.82-7.75 (m, 1H), 7.31-7.23 (m, 1H), 5.80 (s, 2H), 2.44 (s, 3H).Carboxylic acid proton not observed.

Example 294:6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((6-(fluoro-18F)pyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine

[¹⁸F]fluoride in a shipping vial (obtained from the cyclotron facility)was transferred onto and trapped on an ion exchange cartridge. It wasthen eluted into the reaction vessel (RV1) of a Synthra RNPlus® modulewith a solution of potassium bicarbonate (1.09 mg, 0.011 mmol) andKryptofix 222 (7.2 mg, 0.019 mmol) in 0.8 mL of acetonitrile/water (6/2,v/v). The solvent was evaporated under a stream of Nitrogen at 85° C.and under vacuum. Anhydrous CH₃CN (0.5 mL) was added and the aboveprocess was repeated with the temperature increased to 110° C. for 3.5min. The reaction vial was then cooled to 70° C. before a solution of(3.0 mg, 0.0069 mmol) of1-((6-bromopyridin-3-yl)methyl)-6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 68) in anhydrous NMP (0.7 mL) was added to reactionvessel. The reaction mixture was heated at 120° C. for 10 min. Thereactor was then cooled to 40° C. and diluted with water (4.3 mL) andthe contents was transferred into the HPLC injector loop forpurification.

Purification was performed by HPLC using a semi-preparative EclipseXDB-C18 column (5 μm, 9.4 mm×250 mm) with a mixture of 10 mM NH₄OAc andMeCN (53:47 v/v) at a flow rate of 4 mL/min with UV detection at 254 nm.The purified radiotracer solution was diluted with 30 mL of water andpassed through a SepPak Light C-18 cartridge. The C-18 cartridge wasfurther washed with 10 mL of water before 0.5 mL EtOH was used to elutethe tracer. The tracer solution was further diluted with 4.5 mL ofsaline. The final formulation contains an ethanol concentration of 10%,suitable for intravenous injection (IV).

Example 295:2-((6-(3-(Difluoromethyl)-4-fluorophenyl-1,2,3,4,5,6-¹³C₆)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole

The title compound was prepared in a manner analogous to Example 10using2-(3-(difluoromethyl)-4-fluorophenyl-1,2,3,4,5,6-¹³C₆)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(Intermediate 67) and Intermediate 19:2-((6-Bromo-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole.MS (ESI): mass calcd. for C₁₁ ¹³C₆H₁₂F₃N₅O, 365.12; m/z found, 3668.1[M+H]⁺.

Example 296:2-[[3-Deuterio-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole

Step A.2-((3-Bromo-6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole.The title compound was prepared in a manner analogous to Example 8 using3-bromo-6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridine(Intermediate 66) and 2-(chloromethyl)-5-methyl-1,3,4-oxadiazole. MS(ESI): mass calcd. for C₁₇H₁₁BrF₃N₅O, 437.0; m/z found, 438.1 [M+H]⁺. ¹HNMR (500 MHz, Chloroform-d) δ 8.85 (d, J=1.9 Hz, 1H), 8.00 (d, J=1.8 Hz,1H), 7.85-7.82 (m, 1H), 7.75-7.70 (m, 1H), 7.34-7.28 (m, 1H), 6.98 (t,J=54.8 Hz, 1H), 5.80 (s, 2H), 2.51 (s, 3H).

Step B.2-[[3-Deuterio-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole.Pd/C (10%, 36 mg, 0.03 mmol) was added to a mixture of2-((3-bromo-6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-5-methyl-1,3,4-oxadiazole(15 mg, 0.03 mmol) and DIPEA (59 μL. 0.3 mmol) in DMF (1 mL) at roomtemperature. Upon addition of Pd/C, the reaction mixture was purged withD2 gas (99.96 atom % D). After 10 minutes, the reaction mixture waspurged with nitrogen and filtered. The filtrate was concentrated underreduced pressure and purification (FCC, SiO₂, 0-99% EtOAc in hexanes)afforded the title compound (6 mg, 47%, H:D 0.09:1.00). MS (ESI): masscalcd. for C₁₇H₁₁DF₃N₅O, 360.1; m/z found, 361.1 [M+H]⁺. ¹H NMR (500MHz, Chloroform-d) δ 8.82 (d, J=1.9 Hz, 1H), 7.99 (d, J=1.9 Hz, 1H),7.87-7.83 (m, 1H), 7.76-7.71 (m, 1H), 7.33-7.27 (m, 1H), 6.98 (t, J=54.8Hz, 1H), 5.83 (s, 2H), 2.50 (s, 3H).

BIOLOGICAL ASSAYS Effects of Test Articles on Cloned Human NR1/GluN2BIon Channels Expressed in Mammalian Cells

NMDA receptors are ion channels that are highly permeable to Ca²⁺ ions,rendering it possible to monitor NMDA receptor function using cell-basedcalcium flux assay. In this assay, co-agonists glutamate and glycine areadded to cells heterologously expressing human GluN1/GluN2B NMDAreceptors to initiate cellular Ca²⁺ influx. The time course of thechanges in intracellular calcium is measured using a fluorescent dye anda FLIPR (Fluorometric Imaging Plate Reader) device.

Twenty-four hours before measurements, the expression of the NMDAreceptors in the stable cell line is induced with Tet-On induciblesystem in the presence of a non-selective NMDA receptor blocker. On theday of the experiment, cell culture media is carefully washed, and thecells are loaded with Calcium 5 Dye Kit (Molecular Devices) in dyeloading buffer containing 137 mM NaCl, 4 mM KCl, 2 mM CaCl₂), 0.5 mMMgCl₂ (standard assay) or 1.5 mM MgCl₂ (HTS assay), 10 mM HEPES and 5 mMD-glucose; pH 7.4. After 1 h incubation at the room temperature, the dyeis washed away with the assay buffer (137 mM NaCl (standard assay) or150 mM (HTS assay), 4 mM KCl (standard assay) or 3 mM (HTS assay), 2 mMCaCl₂), 0.01 mM EDTA, 10 mM HEPES and 5 mM D-glucose; pH 7.4) In theFLIPR TETRA reader, various concentrations of the test compounds areadded to the cells for 5 min while fluorescence is monitored to detectpotential agonist activity. Next, co-agonists, glutamate and glycine areadded for another 5 minutes. The concentration of glutamatecorresponding to ˜EC₄₀ (standard assay) or EC₄₀ (HTS assay) is used tomaximize the assay's signal window and ability to detect NMDA receptorantagonists and negative allosteric modulators. A saturatingconcentration (10 μM) of glycine is also present in the assay. Anon-selective NMDA receptor antagonist, (+)MK-801 is used as a positivecontrol for antagonist activity. The fluorescent signal in the presenceof test compounds is quantified and normalized to the signal defined bythe appropriate control wells.

TABLE 3 GluN2B IC50 Ex # Compound Name (μM) 11-(Pyrimidin-2-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-0.800 b]pyridine; 2 1-[(5-Bromo-3-pyridyl)methyl]-6-[3- 0.329(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 35-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1- 0.483yl]methyl]pyridine-3-carbonitrile; 41-[(2-Methylpyrimidin-5-yl)methyl]-6-[3- 4.670(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 51-(Pyrazin-2-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3- 0.237b]pyridine; 61-(Pyrimidin-4-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-0.819 b]pyridine; 72-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-0.748 1,3,4-oxadiazole; 82-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.028 yl]methyl]-5-methyl-oxazole; 92-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1- 0.078yl]methyl]-5-methyl-oxazole; 102-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.019 yl]methyl]-5-methyl-1,3,4-oxadiazole; 116-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(1H-pyrazol-4- 0.486ylmethyl)pyrazolo[4,3-b]pyridine; 126-[3-(1,1-Difluoroethyl)phenyl]-1-(3-pyridylmethyl)pyrazolo[4,3- 0.026b]pyridine; 136-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-methyl-4H-1,2,4-triazol-1.960 3-yl)methyl]pyrazolo[4,3-b]pyridine; 141-[(3-Methyl-1H-pyrazol-5-yl)methyl]-6-[3- 4.740(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 155-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1- >2.99yl]methyl]-N-methyl-1,3,4-thiadiazol-2-amine; 165-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-1.050 yl]methyl]-1,3,4-thiadiazol-2-amine; 175-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.064 yl]methyl]-1,3,4-thiadiazol-2-ol; 185-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-3.550 yl]methyl]-1,3,4-thiadiazol-2-amine; 19N-(5-((6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3- >2.99b]pyridin-1-yl)methyl)-1,3,4-thiadiazol-2-yl)acetamide; 203-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-0.751 1,2,4-oxadiazole; 211-Benzyl-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 3.280 221-[(3-Fluorophenyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-1.820 b]pyridine; 233-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1- 0.400yl]methyl]benzonitrile; 24 1-[(4-Methoxyphenyl)methyl]-6-[3- 7.930(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 256-[3-(Trifluoromethyl)phenyl]-1-[[4- >10(trifluoromethyl)phenyl]methyl]pyrazolo[4,3-b]pyridine; 263-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.062 yl]methyl]benzonitrile; 276-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(3,5- 0.394difluorophenyl)methyl]pyrazolo[4,3-b]pyridine; 283-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.125 yl]methyl]-5-fluoro-benzonitrile; 293-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.065 yl]methyl]benzonitrile; 306-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(3,5- 0.536difluorophenyl)methyl]pyrazolo[4,3-b]pyridine; 313-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.389 yl]methyl]-5-fluoro-benzonitrile; 326-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-methyl-2- >2.99thienyl)methyl]pyrazolo[4,3-b]pyridine; 336-(3-(Difluoromethyl)-4-fluorophenyl)-1-((5-fluorothiophen-2- 1.030yl)methyl)-1H-pyrazolo[4,3-b]pyridine; 345-((6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-0.353 1-yl)methyl)thiophene-2-carbonitrile; 356-[3-(1,1-Difluoroethyl)phenyl]-1-(1H-pyrazol-4- 0.648ylmethyl)pyrazolo[4,3-b]pyridine; 361-[(1-Methylimidazol-4-yl)methyl]-6-[3- 0.668(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 371-[(2,5-Dimethylpyrazol-3-yl)methyl]-6-[3- 3.950(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 386-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(1H-pyrazol-4- 0.226ylmethyl)pyrazolo[4,3-b]pyridine; 396-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(1-methylpyrazol-3- 0.271yl)methyl]pyrazolo[4,3-b]pyridine; 406-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-(1H-pyrazol-4- 0.825ylmethyl)pyrazolo[4,3-b]pyridine; 416-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(1H-pyrazol-4- 0.423ylmethyl)pyrazolo[4,3-b]pyridine; 425-[[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-0.475 isoxazole; 433-[[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-0.139 isoxazole; 443-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1- 0.165yl]methyl]isoxazole; 453-[[6-[3-(1,1-Difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1- 0.044yl]methyl]-5-methyl-isoxazole; 464-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1- 0.538yl]methyl]oxazole; 475-Methyl-3-[[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-0.148 yl]methyl]isoxazole; 485-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-0.113 2-methyl-oxazole; 492-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-0.053 5-methyl-oxazole; 505-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.031 yl]methyl]isoxazole; 513-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.023 yl]methyl]isoxazole; 525-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.022 yl]methyl]-3-methyl-isoxazole; 533-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.018 yl]methyl]-5-methyl-isoxazole; 545-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.133 yl]methyl]-2-methyl-oxazole; 554-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.285 yl]methyl]-2-methyl-oxazole; 563-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.056 yl]methyl]-4-methyl-isoxazole; 574-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.082 yl]methyl]-3,5-dimethyl-isoxazole; 583-[[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.158 yl]methyl]-5-methyl-isoxazole; 593-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.061 yl]methyl]-5-methyl-isoxazole; 605-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.559 yl]methyl]-2-methyl-oxazole; 612-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.160 yl]methyl]-5-methyl-oxazole; 623-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-0.159 yl]methyl]-5-methyl-isoxazole; 635-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1- 0.268yl]methyl]-2-methyl-oxazole; 645-Methyl-3-[[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-2.240 yl]methyl]isothiazole; 652-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.084 yl]methyl]-5-methyl-thiazole; 662-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.410 yl]methyl]-4-methyl-thiazole; 674-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.466 yl]methyl]-2-methyl-thiazole; 682-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-0.265 5-methyl-thiazole; 692-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.104 yl]methyl]-5-methyl-thiazole; 702-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1- 0.350yl]methyl]-5-methyl-thiazole; 711-[(1-Methyl-1,2,4-triazol-3-yl)methyl]-6-[3- 0.891(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 726-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(1-methyltriazol-4- 0.827yl)methyl]pyrazolo[4,3-b]pyridine; 736-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(1-methyl-1,2,4-triazol-3-0.383 yl)methyl]pyrazolo[4,3-b]pyridine; 746-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(4-methyl-1,2,4-triazol-3-0.111 yl)methyl]pyrazolo[4,3-b]pyridine; 756-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(4,5-dimethyl-1,2,4-triazol-0.139 3-yl)methyl]pyrazolo[4,3-b]pyridine; 766-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-ethyl-4-methyl-1,2,4- 3.830triazol-3-yl)methyl]pyrazolo[4,3-b]pyridine; 772-[[6-(5-Chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5- 0.089methyl-1,3,4-oxadiazole; 782-Methyl-5-[[6-[5-(trifluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-0.143 1-yl]methyl]-1,3,4-oxadiazole; 792-[[6-[5-(Difluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1- 0.153yl]methyl]-5-methyl-1,3,4-oxadiazole; 805-[[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-0.957 1,2,4-oxadiazole; 815-[[6-(3-Methoxyphenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-3- 2.310methyl-1,2,4-oxadiazole; 822-[[6-[3-(1,1-Difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1- 0.160yl]methyl]-5-methyl-1,3,4-oxadiazole; 832-[[6-[3-(1,1-Difluoroethyl)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-0.126 yl]methyl]-5-methyl-1,3,4-oxadiazole; 843-Methyl-5-[[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-0.293 yl]methyl]-1,2,4-oxadiazole; 852-Methyl-5-[[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-0.143 yl]methyl]-1,3,4-oxadiazole; 865-Methyl-3-[[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-0.202 yl]methyl]-1,2,4-oxadiazole; 875-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-0.383 1,2,4-oxadiazole; 882-Methyl-5-[[6-[2-(trifluoromethyl)-4-pyridyl]pyrazolo[4,3-b]pyridin-0.467 1-yl]methyl]-1,3,4-oxadiazole; 892-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-0.037 5-methyl-1,3,4-oxadiazole; 902-[[3-Fluoro-6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1- 0.033yl]methyl]-5-methyl-1,3,4-oxadiazole; 912-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-0.145 5-(trifluoromethyl)-1,3,4-oxadiazole; 922-[[6-(3-Chloro-4-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-0.090 5-methyl-1,3,4-oxadiazole; 932-[[6-(3-Chloro-4-fluoro-phenyl)-3-fluoro-pyrazolo[4,3-b]pyridin-1-0.087 yl]methyl]-5-methyl-1,3,4-oxadiazole; 942-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.058 yl]methyl]-1,3,4-oxadiazole; 955-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.040 yl]methyl]-3-methyl-1,2,4-oxadiazole; 962-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3- 0.038b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 973-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.041 yl]methyl]-5-methyl-1,2,4-oxadiazole; 983-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.034 yl]methyl]-4-methyl-1,2,5-oxadiazole; 992-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-0.070 b]pyridin-1-yl]methyl]-1,3,4-oxadiazole; 1002-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.550 yl]methyl]-5-isopropyl-1,3,4-oxadiazole; 1015-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1- >2.99yl]methyl]-N,N-dimethyl-1,3,4-oxadiazol-2-amine; 1022-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.049 yl]methyl]-5-(trifluoromethyl)-1,3,4-oxadiazole; 1032-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1- >2.99yl]methyl]-5-phenyl-1,3,4-oxadiazole; 1042-[[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.244 yl]methyl]-5-methyl-1,3,4-oxadiazole; 1052-[[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-0.367 b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 1062-[[6-[4-Chloro-3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1- 0.115yl]methyl]-5-methyl-1,3,4-oxadiazole; 1072-[[6-[4-Chloro-3-(difluoromethyl)phenyl]-3-fluoro-pyrazolo[4,3- 0.347b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 1085-[[6-[3-Fluoro-5-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-0.815 yl]methyl]-3-methyl-1,2,4-oxadiazole; 1095-[[6-[2-Fluoro-5-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-3.260 yl]methyl]-3-methyl-1,2,4-oxadiazole; 1105-[[6-[4-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-0.400 yl]methyl]-3-methyl-1,2,4-oxadiazole; 1115-[[6-[2-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-0.183 yl]methyl]-3-methyl-1,2,4-oxadiazole; 1125-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.289 yl]methyl]-3-methyl-1,2,4-oxadiazole; 1132-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.104 yl]methyl]-5-methyl-1,3,4-oxadiazole; 1143-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.279 yl]methyl]-5-methyl-1,2,4-oxadiazole; 1152-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.414 yl]methyl]-5-(trifluoromethyl)-1,3,4-oxadiazole; 1162-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-0.283 yl]methyl]-5-methyl-1,3,4-oxadiazole; 1172-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]-3-fluoro-pyrazolo[4,3- 0.655b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 1182-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1- 0.035yl]methyl]-5-methyl-1,3,4-oxadiazole; 1192-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1- 0.245yl]methyl]-5-(trifluoromethyl)-1,3,4-oxadiazole; 1204-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1- 0.895yl]methyl]thiadiazole; 1212-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.025 yl]methyl]-1,3,4-thiadiazole; 1222-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.018 yl]methyl]-5-methyl-1,3,4-thiadiazole; 1232-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3- 0.042b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole; 1242-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-methyl-pyrazolo[4,3- 0.066b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole; 1252-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.138 yl]methyl]-5-ethyl-1,3,4-thiadiazole; 1265-((6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1.620 1-yl)methyl)-N-methyl-1,3,4-thiadiazol-2-amine; 1272-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.850 yl]methyl]-5-methoxy-1,3,4-thiadiazole; 128N-(5-((6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3- >2.99b]pyridin-1-yl)methyl)-1,3,4-thiadiazol-2-yl)acetamide; 1292-(Difluoromethyl)-5-[[6-[3-(difluoromethyl)-4-fluoro- 0.017phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazole; 1302-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-0.123 b]pyridin-1-yl]methyl]-1,3,4-thiadiazole; 1312-[[6-[4-Chloro-3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1- 0.057yl]methyl]-5-methyl-1,3,4-thiadiazole; 1322-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-0.033 5-methyl-1,3,4-thiadiazole; 1332-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.072 yl]methyl]-5-methyl-1,3,4-thiadiazole; 1342-[[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-1.320 yl]methyl]-5-methoxy-1,3,4-thiadiazole; 1352-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-0.133 yl]methyl]-5-methyl-1,3,4-thiadiazole; 1362-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1- 0.017yl]methyl]-5-methyl-1,3,4-thiadiazole; 1376-(4-Methyl-2-thienyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine; 0.116138 1-[(5-Methyl-3-pyridyl)methyl]-6-(4-methyl-2-thienyl)pyrazolo[4,3-0.159 b]pyridine; 1396-(5-Methyl-2-thienyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine; 0.089140 5-[[6-(5-Chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1- 0.170yl]methyl]pyridine-3-carbonitrile; 1416-(3-Chloro-2-thienyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine; 0.061142 5-[[6-[5-(Difluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1- 0.219yl]methyl]pyridine-3-carbonitrile; 1431-((6-Fluoropyridin-3-yl)methyl)-6-(5-(trifluoromethyl)thiophen-2-yl)-0.132 1H-pyrazolo[4,3-b]pyridine; 1445-[[6-[5-(Trifluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1- 0.582yl]methyl]pyridine-3-carbonitrile; 1451-[(6-Fluoro-3-pyridyl)methyl]-6-(m-tolyl)pyrazolo[4,3-b]pyridine; 0.036146 1-[(5-Fluoro-3-pyridyl)methyl]-6-(m-tolyl)pyrazolo[4,3-b]pyridine;0.009 1473-Fluoro-1-[(5-fluoro-3-pyridyl)methyl]-6-(m-tolyl)pyrazolo[4,3- 0.048b]pyridine; 1486-(4-Chlorophenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3- 0.634b]pyridine; 1496-(4-Fluorophenyl)-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine; 3.460 1506-(4-Fluorophenyl)-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3- 0.410b]pyridine; 151 1-[[5-(Difluoromethoxy)-3-pyridyl]methyl]-6-(4- 1.150fluorophenyl)pyrazolo[4,3-b]pyridine; 1526-(3-Fluorophenyl)-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine; 2.180 1536-(2-Fluorophenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3- 0.720b]pyridine; 1546-(3-Methoxyphenyl)-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine; 7.371155 1-[(6-Fluoro-3-pyridyl)methyl]-6-(3-methoxyphenyl)pyrazolo[4,3-1.650 b]pyridine; 1566-[3-(Difluoromethyl)phenyl]-1-(2-pyridylmethyl)pyrazolo[4,3- 0.740b]pyridine; 1575-[[6-[3-(Difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1- 0.064yl]methyl]pyridine-3-carbonitrile; 1581-[(5-Chloro-3-pyridyl)methyl]-6-[3- 0.014(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 1596-[3-(Difluoromethoxy)phenyl]-1-[(5-fluoro-3- 0.249pyridyl)methyl]pyrazolo[4,3-b]pyridine; 1606-[3-(1,1-Difluoroethyl)phenyl]-1-[(5-methyl-3- 0.112pyridyl)methyl]pyrazolo[4,3-b]pyridine; 1616-[3-(1,1-Difluoroethyl)phenyl]-1-[(5-fluoro-3- 0.040pyridyl)methyl]pyrazolo[4,3-b]pyridine; 1621-(2-Pyridylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3- 0.930b]pyridine; 1631-(3-Pyridylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3- 0.090b]pyridine; 1641-(4-Pyridylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3- 0.798b]pyridine; 165 1-[(6-Methyl-3-pyridyl)methyl]-6-[3- 2.170(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 1661-[(2-Methyl-3-pyridyl)methyl]-6-[3- 0.870(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 1671-[(5-Methyl-3-pyridyl)methyl]-6-[3- 0.250(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 1681-[(4-Methyl-3-pyridyl)methyl]-6-[3- 0.161(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 1691-[(6-Fluoro-3-pyridyl)methyl]-6-[3- 0.234(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 1701-[(2-Fluoro-3-pyridyl)methyl]-6-[3- 1.040(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 1711-[(5-Fluoro-3-pyridyl)methyl]-6-[3- 0.212(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 1721-[(2-Methoxy-3-pyridyl)methyl]-6-[3- 7.780(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 1731-[(5-Methoxy-3-pyridyl)methyl]-6-[3- 0.210(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 1746-[3-(Trifluoromethyl)phenyl]-1-[[6-(trifluoromethyl)-3- 11.899pyridyl]methyl]pyrazolo[4,3-b]pyridine; 1756-[3-(Trifluoromethyl)phenyl]-1-[[5-(trifluoromethyl)-3- 2.300pyridyl]methyl]pyrazolo[4,3-b]pyridine; 1766-[3-(Trifluoromethyl)phenyl]-1-[[4-(trifluoromethyl)-3- 1.300pyridyl]methyl]pyrazolo[4,3-b]pyridine; 1776-(4-Fluoro-3-methyl-phenyl)-1-(3-pyridylmethyl)pyrazolo[4,3- 0.023b]pyridine; 178 3-Fluoro-6-(4-fluoro-3-methyl-phenyl)-1-(3- 0.026pyridylmethyl)pyrazolo[4,3-b]pyridine; 1796-(4-Fluoro-3-methyl-phenyl)-1-[(2-methyl-3- 0.507pyridyl)methyl]pyrazolo[4,3-b]pyridine; 1806-(4-Fluoro-3-methyl-phenyl)-1-[(5-methyl-3- 0.062pyridyl)methyl]pyrazolo[4,3-b]pyridine; 1816-(4-Fluoro-3-methyl-phenyl)-1-[(4-methyl-3- 0.113pyridyl)methyl]pyrazolo[4,3-b]pyridine; 1826-(4-Fluoro-3-methyl-phenyl)-1-[(6-fluoro-3- 0.064pyridyl)methyl]pyrazolo[4,3-b]pyridine; 1836-(4-Fluoro-3-methyl-phenyl)-1-[(5-fluoro-3- 0.021pyridyl)methyl]pyrazolo[4,3-b]pyridine; 1846-(3,5-Difluorophenyl)-1-[(4-methyl-3-pyridyl)methyl]pyrazolo[4,3- 0.068b]pyridine; 1856-(3,5-Difluorophenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3- 0.045b]pyridine; 1866-(3,4-Difluorophenyl)-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine; 2.520187 6-(3,4-Difluorophenyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine;0.218 1886-(3,4-Difluorophenyl)-1-[(2-methyl-3-pyridyl)methyl]pyrazolo[4,3- 3.620b]pyridine; 1896-(3,4-Difluorophenyl)-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3- 0.070b]pyridine; 1906-(3,4-Difluorophenyl)-1-[(4-methyl-3-pyridyl)methyl]pyrazolo[4,3- 0.158b]pyridine; 1916-(3,4-Difluorophenyl)-1-[(6-fluoro-3-pyridyl)methyl]pyrazolo[4,3- 0.176b]pyridine; 1926-(3,4-Difluorophenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3- 0.048b]pyridine; 1936-(3,4-Difluorophenyl)-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-0.277 b]pyridine; 194 1-[[5-(Difluoromethoxy)-3-pyridyl]methyl]-6-(3,4-0.850 difluorophenyl)pyrazolo[4,3-b]pyridine; 1956-(3-Chloro-4-fluoro-phenyl)-1-[(5-fluoro-3- 0.025pyridyl)methyl]pyrazolo[4,3-b]pyridine; 1966-(3-Chloro-4-fluoro-phenyl)-1-[(5-methoxy-3- 0.152pyridyl)methyl]pyrazolo[4,3-b]pyridine; 1976-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(2- 0.130pyridylmethyl)pyrazolo[4,3-b]pyridine; 1986-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(3- 0.008pyridylmethyl)pyrazolo[4,3-b]pyridine; 1996-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-methyl-1-(3- 0.034pyridylmethyl)pyrazolo[4,3-b]pyridine; 2006-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-methyl-3- 0.012pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2016-(3-(difluoromethyl)-4-fluorophenyl)-1-((6-fluoropyridin-3- 0.016yl)methyl)-1H-pyrazolo[4,3-b]pyridine; 2026-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-fluoro-3- 0.014pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2035-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.031 yl]methyl]pyridine-3-carbonitrile; 2046-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(6-methoxy-3- 1.620pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2056-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(6-methoxy-2- 0.177pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2066-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(2-methoxy-3- 0.307pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2076-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-methoxy-3- 0.028pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2081-[(5-Chloro-3-pyridyl)methyl]-6-[3-(difluoromethyl)-4-fluoro- 0.026phenyl]pyrazolo[4,3-b]pyridine; 2096-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[[5-(difluoromethyl)-3- 0.020pyridyl]methyl]pyrazolo[4,3-b]pyridine; 2101-[[5-(Difluoromethoxy)-3-pyridyl]methyl]-6-[3-(difluoromethyl)-4- 0.110fluoro-phenyl]pyrazolo[4,3-b]pyridine; 2116-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[[5-(trifluoromethyl)-3- 0.047pyridyl]methyl]pyrazolo[4,3-b]pyridine; 2125-[[6-[3-(Difluoromethyl)-2-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.067 yl]methyl]pyridine-3-carbonitrile; 2131-[(5-Chloro-3-pyridyl)methyl]-6-[3-(difluoromethyl)-2-fluoro- 0.068phenyl]pyrazolo[4,3-b]pyridine; 2146-(3,4-Dichlorophenyl)-1-[(6-fluoro-3-pyridyl)methyl]pyrazolo[4,3- 1.910b]pyridine; 2156-(3,4-Dichlorophenyl)-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-0.217 b]pyridine; 216 6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-(3-0.109 pyridylmethyl)pyrazolo[4,3-b]pyridine; 2176-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-[(5-methyl-3- 0.189pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2186-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-[(5-fluoro-3- 0.107pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2195-[[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.158 yl]methyl]pyridine-3-carbonitrile; 2206-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-[(5-methoxy-3- 0.089pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2211-[(5-Chloro-3-pyridyl)methyl]-6-[3-(1,1-difluoroethyl)-4-fluoro- 0.064phenyl]pyrazolo[4,3-b]pyridine; 2226-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(2- 0.502pyridylmethyl)pyrazolo[4,3-b]pyridine; 2236-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(3- 0.038pyridylmethyl)pyrazolo[4,3-b]pyridine; 2246-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(5-methyl-3- 0.056pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2256-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(5-fluoro-3- 0.039pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2265-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-0.068 yl]methyl]pyridine-3-carbonitrile; 2276-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(6-methoxy-3- 1.620pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2286-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(6-methoxy-2- 0.383pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2296-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(2-methoxy-3- 0.716pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2306-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(5-methoxy-3- 0.048pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2311-[(5-Chloro-3-pyridyl)methyl]-6-[3-(difluoromethoxy)-4-fluoro- 0.039phenyl]pyrazolo[4,3-b]pyridine; 2326-[4-Chloro-3-(Difluoromethyl)phenyl]-1-[(5-methoxy-3- 0.040pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2331-[(5-Fluoro-3-pyridyl)methyl]-6-[4-fluoro-3- 0.075(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 2346-[4-Fluoro-3-(trifluoromethyl)phenyl]-1-[(5-methoxy-3- 0.092pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2356-(3-Bromo-4-fluorophenyl)-1-((6-fluoropyridin-3-yl)methyl)-1H- 0.253pyrazolo[4,3-b]pyridine; 2365-[[6-[4-Chloro-3-(1,1-difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-0.494 yl]methyl]pyridine-3-carbonitrile; 2376-[4-Chloro-3-(1,1-difluoroethyl)phenyl]-1-[(5-chloro-3- 0.200pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2386-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(3- 0.117pyridylmethyl)pyrazolo[4,3-b]pyridine; 2396-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(5-methyl-3- 0.120pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2406-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(5-fluoro-3- 0.166pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2415-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-0.151 yl]methyl]pyridine-3-carbonitrile; 2426-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(5-methoxy-3- 0.500pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2436-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(5-chloro-3- 0.146pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2446-(2,4-Difluoro-3-methyl-phenyl)-1-(2-pyridylmethyl)pyrazolo[4,3- 0.310b]pyridine; 2456-(2,4-Difluoro-3-methyl-phenyl)-1-(3-pyridylmethyl)pyrazolo[4,3- 0.033b]pyridine; 246 6-(2,4-Difluoro-3-methyl-phenyl)-1-[(5-methyl-3- 0.052pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2476-(2,4-Difluoro-3-methyl-phenyl)-1-[(4-methyl-3- 0.128pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2486-(2,4-Difluoro-3-methyl-phenyl)-1-[(6-fluoro-3- 0.062pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2496-(2,4-Difluoro-3-methyl-phenyl)-1-[(5-fluoro-3- 0.040pyridyl)methyl]pyrazolo[4,3-b]pyridine; 2501-(2-Pyridylmethyl)-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine;2.630 2511-[(5-Fluoro-3-pyridyl)methyl]-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-0.025 b]pyridine; 252 1-[(5-Methoxy-3-pyridyl)methyl]-6-(3,4,5- 0.382trifluorophenyl)pyrazolo[4,3-b]pyridine; 2531-[[5-(Difluoromethoxy)-3-pyridyl]methyl]-6-(3,4,5- 0.980trifluorophenyl)pyrazolo[4,3-b]pyridine; 2541-(Pyridazin-4-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-0.548 b]pyridine; 2556-(m-Tolyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine; 0.329 2566-(3-Fluorophenyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine;1.410 2576-[3-(1,1-Difluoroethyl)phenyl]-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-0.110 b]pyridine; 2581-(Pyridazin-3-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-0.240 b]pyridine; 2596-(4-Fluoro-3-methyl-phenyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3- 0.030b]pyridine; 2606-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-(pyridazin-3- 0.162ylmethyl)pyrazolo[4,3-b]pyridine; 2616-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(pyridazin-3- 0.023ylmethyl)pyrazolo[4,3-b]pyridine; 2626-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(6-methylpyridazin-3- 0.273yl)methyl]pyrazolo[4,3-b]pyridine; 2636-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(pyridazin-3- 0.112ylmethyl)pyrazolo[4,3-b]pyridine; 2646-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(6-methylpyridazin-3- 0.626yl)methyl]pyrazolo[4,3-b]pyridine; 2656-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(pyridazin-3- 0.115ylmethyl)pyrazolo[4,3-b]pyridine; 2666-(3,4-Difluorophenyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3- 0.670b]pyridine; 2676-(4-Chloro-3-methyl-phenyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3- 0.404b]pyridine; 2681-(Pyridazin-3-ylmethyl)-6-(3,4,5-trifluorophenyl)pyrazolo[4,3- 0.673b]pyridine; 269 6-(2,4-Difluoro-3-methyl-phenyl)-1-(pyridazin-3- 0.108ylmethyl)pyrazolo[4,3-b]pyridine; 2706-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(pyrimidin-4- 0.176ylmethyl)pyrazolo[4,3-b]pyridine; 2716-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(pyrimidin-4- 0.401ylmethyl)pyrazolo[4,3-b]pyridine; 2726-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(pyrazin-2- 0.037ylmethyl)pyrazolo[4,3-b]pyridine; 2736-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(pyrazin-2- 0.320ylmethyl)pyrazolo[4,3-b]pyridine; 2746-[3-(1,1-Difluoroethyl)phenyl]-1-(pyrimidin-5- 0.051ylmethyl)pyrazolo[4,3-b]pyridine; 2756-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(pyrimidin-5- 0.012ylmethyl)pyrazolo[4,3-b]pyridine; 2761-(Pyrimidin-5-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-0.145 b]pyridine; 2776-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-(pyrimidin-5- 0.065ylmethyl)pyrazolo[4,3-b]pyridine; 2786-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(pyrimidin-5- 0.052ylmethyl)pyrazolo[4,3-b]pyridine; 2796-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(pyrimidin-5- 0.090ylmethyl)pyrazolo[4,3-b]pyridine; 2806-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(6-methylpyrimidin-4- 0.226yl)methyl]pyrazolo[4,3-b]pyridine; 2816-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(6-methylpyrimidin-4- 0.984yl)methyl]pyrazolo[4,3-b]pyridine; 2826-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(2-methylpyrimidin-4- 0.387yl)methyl]pyrazolo[4,3-b]pyridine; 2831-[(2-Methylpyrimidin-4-yl)methyl]-6-[3- 3.250(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 2846-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(2-methylpyrimidin-4- 0.942yl)methyl]pyrazolo[4,3-b]pyridine; 2856-(3,4-Difluorophenyl)-1-[(2-methylpyrimidin-5- >10yl)methyl]pyrazolo[4,3-b]pyridine; 2866-(4-Chloro-3-methyl-phenyl)-1-[(2-methylpyrimidin-5- 3.016yl)methyl]pyrazolo[4,3-b]pyridine; 2871-[(5-Methylpyrimidin-2-yl)methyl]-6-[3- 3.243(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine; 2886-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(6-methoxypyrimidin-4- 0.182yl)methyl]pyrazolo[4,3-b]pyridine; 2896-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(6-methoxypyrimidin-4- 0.350yl)methyl]pyrazolo[4,3-b]pyridine; 2906-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(2-methoxypyrimidin-4- 0.320yl)methyl]pyrazolo[4,3-b]pyridine; 2916-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(2-methoxypyrimidin-4- 0.938yl)methyl]pyrazolo[4,3-b]pyridine; 292(5-((6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-0.170 1-yl)methyl)-1,3,4-oxadiazol-2-yl)methanol; 2932-Fluoro-5-(1-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-1H- >10pyrazolo[4,3-b]pyridin-6-yl)benzoic acid; 2946-(3-(Difluoromethyl)-4-fluorophenyl)-1-((6-(fluoro-18F)pyridin-3- NTyl)methyl)-1H-pyrazolo[4,3-b]pyridine; 2952-[[3-Bromo-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3- NTb]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole; 2962-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1- NTyl]methyl]-5-methyl-1,3,4-oxadiazole; and 2972-[[3-Deuterio-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3- 0.024b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole. NT means not tested.

Protocol for Liver Microsomal Stability (Extraction Ratio)

Liver Microsomal Stability. Microsomal stability studies (Chrovian etal, “1H-Pyrrolo[3,2-b]pyridine GluN2B-Selective Negative AllostericModulators”. ACS Med Chem Lett. 2019 Jan. 10; 10(3):261-266) wereconducted on a Biomek® FX Robotic Liquid Handling Workstation (BeckmanCoulter, Brea, Calif.), which consists of a 96-channel pipette head, a12-position workstation deck, and a plate incubator. Test compounds (1μm) were spiked in a reaction mix consisting of 100 mM potassiumphosphate buffer (pH 7.4), 3 mM MgCl₂, and 0.5 mg/mL liver microsomesfrom mouse, rat, and human (BD Gentest). The reaction was brought to 37°C. and initiated by adding NADPH to a final concentration of 1 mM. Aftermixing on the platedeck, 50 L aliquots were excised from the reactionplate at 0, 5, 10, 20, 40, and 60 min and quenched with four volumes ofacetonitrile spiked with 500 μg/nL of the internal standard phenytoin.Quenched plates were centrifuged at 5700 rpm for 10 min at 4° C., andsupernatant was diluted 1:3 in water before LC/MS/MS analysis. Thecompound half-lives were derived from plots of the ln of percentremaining compound over time to determine the intrinsic clearance. Thepredicted hepatic clearance was derived from the intrinsic clearancevalue using equations from the well-stirred model (Current DrugMetabolism, 2008, 9, 940-951), where no correction was made plasmaprotein binding and the blood to plasma concentration ratio was assumedto be one. The extraction ratio (ER) was calculated by dividing thepredicted hepatic clearance by species blood flow (Q), where Q is 90,55, and 21.7 mL/min/kg for mouse, rat and human, respectively.

Results of the assay performed on the compounds of Examples are shown inTable 4.

Example # Extraction Ratio @ 1 μM 8 0.68 10 0.31 52 0.69 96 <0.298 970.42 122 0.60 198 0.65 202 0.57 261 <0.298 275 0.36

Specific Embodiments

The present disclosure is exemplified by specific embodiments 1-54below.

-   1. A compound having the structure of Formula (I):

-   -   wherein    -   R¹ is H, halo, or CH₃;    -   Ar¹ is selected from the group consisting of:        -   (a) phenyl substituted with one member selected from the            group consisting of: halo, C₁₋₆alkyl, OC₁₋₆alkyl,            C₁₋₆perhaloalkyl, and OC₁₋₆perhaloalkyl;        -   (b) phenyl substituted with two or three members each            independently selected from the group consisting of: halo,            C₁₋₆alkyl, C₁₋₆perhaloalkyl, OC₁₋₆perhaloalkyl, and CO₂H;            and        -   (c) thienyl substituted with a member selected from the            group consisting of: halo, C₁₋₆alkyl, and C₁₋₆perhaloalkyl;            and pyridine substituted with CF₃; and    -   R² is selected from the group consisting of:        -   (d)

-   -   -   wherein            -   R^(a) is halo, C₁₋₆alkyl or CN;            -   R^(b) is H or C₁₋₂alkyl;            -   R^(c) is selected from the group consisting of: H,                C₁₋₆alkyl, C₁₋₆perhaloalkyl, CH₂H, OC₁₋₆alkyl, OH, NH₂,                N₂(CH₃), N(CH₃)₂, N(C═O)CH₃, cyclopropyl, and phenyl;            -   X¹ is NCH₃, S or O;            -   X² is O, NH or NCH₃;            -   X³ is O or S;            -   X⁴ is NH or O;            -   X⁵ is NCH₃ or O;            -   X⁶ is NCH₃ or S;            -   and n is 2;        -   (e) phenyl; phenyl substituted with one or two members            independently selected from the group consisting of: halo,            OC₁₋₆alkyl, C₁₋₆perhaloalkyl, and CN; and        -   (f)

-   -   -   wherein            -   R^(d) is H or OC₁₋₆alkyl;            -   R^(e) is a member selected from the group consisting of:                H, halo, C₁₋₆alkyl, C₁₋₆perhaloalkyl, OC₁₋₆alkyl,                OC₁₋₆perhaloalkyl, and CN; and            -   R^(f) is H, C₁₋₆alkyl or OC₁₋₆alkyl;

    -   and pharmaceutically acceptable salts, solvates, stereoisomers,        isotopic variants, or N-oxides thereof.

-   2. The compound of embodiment 1, wherein R¹ is H.

-   3. The compound of embodiment 1, wherein R¹ is F.

-   4. The compound of embodiment 1, wherein R¹ is CH₃.

-   5. The compound of embodiment 1, wherein Ar^(l) is

-   6. The compound of embodiment 1, wherein Ar¹ is phenyl substituted    with F, Cl, CH₃, OCH₃, CF₂H, CF₃, CF₂CH₃, or OCHF₂.-   7. The compound of embodiment 1, wherein Ar¹ is

-   8. The compound of embodiment 1, wherein Ar¹ is phenyl substituted    with two or three members independently selected from the group    consisting of: F, Cl, Br, CH₃, CF₂H, CF₃, CF₂CH₃, or OCHF₂.-   9. The compound of embodiment 1, wherein Ar¹ is

-   10. The compound of embodiment 1, wherein R^(a) is F, CH₃ or CN.-   11. The compound of embodiment 1, wherein R^(b) is H, CH₃ or CH₂CH₃.-   12. The compound of embodiment 1, wherein R^(b) is H or CH₃.-   13. The compound of embodiment 1, wherein R^(c) is H, CH₃, CH₂CH₃,    CF₃, OCH₃, OH, NH₂, NH(CH₃), N(CH₃)₂, NH(C═O)CH₃, cyclopropyl, or    phenyl.-   14. The compound of embodiment 1, wherein R^(d) is H.-   15. The compound of embodiment 1, wherein R^(d) is OCH₃.-   16. The compound of embodiment 1, wherein R^(e) is H, Br, Cl, F,    CH₃, CF₂H, CF₃, OCH₃, OCF₂H, or CN.-   17. The compound of embodiment 1, wherein R^(f) is H, CH₃, or OCH₃.-   18. The compound of embodiment 1, wherein X¹ is NCH₃.-   19. The compound of embodiment 1, wherein X¹ is O.-   20. The compound of embodiment 1, wherein X¹ is S.-   21. The compound of embodiment 1, wherein X² is O.-   22. The compound of embodiment 1, wherein X² is NH.-   23. The compound of embodiment 1, wherein X² is NCH₃.-   24. The compound of embodiment 1, wherein X³ is O.-   25. The compound of embodiment 1, wherein X³ is S.-   26. The compound of embodiment 1, wherein X⁴ is NH.-   27. The compound of embodiment 1, wherein X⁴ is O.-   28. The compound of embodiment 1, wherein X⁵ is NCH₃.-   29. The compound of embodiment 1, wherein X⁵ is O.-   30. The compound of embodiment 1, wherein X⁶ is NCH₃.-   31. The compound of embodiment 1, wherein X⁶ is S.-   32. The compound of embodiment 1, wherein R² is

-   33. The compound of embodiment 1, wherein R² is

-   34. The compound of embodiment 1, wherein R² is

-   35. The compound of embodiment 1, wherein R² is

-   36. The compound of embodiment 1, wherein R² is

-   38. The compound of embodiment 1, wherein R² is

-   39. The compound of embodiment 1, wherein R² is

-   40. The compound of embodiment 1, wherein R² is

-   41. The compound of embodiment 1, wherein R² is

-   42. The compound of embodiment 1, wherein R² is

-   43. The compound of embodiment 1 wherein R² is

-   44. The compound of embodiment 1, and pharmaceutically acceptable    salts, solvates, or N-oxides thereof, having the structure of    Formula (A):

-   -   wherein    -   R¹ is H, F, or 2CH₃;    -   HAL is F or Cl;    -   R^(g) is selected from the group consisting of: H, Cl, CH₃,        CF₂H, CF₂CH₃, CF₃, and OCF₂H;    -   and    -   Ring A is selected from the group consisting of:    -   (a)

-   -    wherein R^(a) is F, CH₃ or CN;    -   (b)

-   -    and    -   (c)

-   -   (d)

-   -   X¹ is O, NCH₃ or S;    -   X³ is O or S;    -   X⁴ is NH or O;    -   X⁵ is NCH₃ or O;    -   R^(b) is H, CH₃, or CH₂CH₃;    -   R^(c) is selected from the group consisting of: H, CH₃, CH₂CH₃,        CH(CH₃)₂, CF₃, CHF₂, OCH₃, OH, NH₂, NH(CH₃), N(CH₃)₂,        NH(C═O)CH₃, cyclopropyl, and phenyl;    -   R^(d) is H or OCH₃; and    -   R_(f) is H, CH₃ or OCH₃.

-   45. The compound of embodiment 44, wherein ring A is

-   46. The compound of embodiment 1, and pharmaceutically acceptable    salts, solvates, or N-oxides thereof, having the structure of    Formula (1B):

-   -   wherein    -   R¹ is H, F, or CH₃;    -   R^(e) is a member selected from the group consisting of: H, Br,        Cl, F, C₁₋₄alkyl, C₁₋₄perhaloalkyl, OC₁₋₄alkyl,        OC₁₋₄perhaloalkyl, and CN; and    -   Ar¹ is selected from the group consisting of:        -   (a) phenyl substituted with one member selected from the            group consisting of: Cl, F, C₁₋₄alkyl, OC₁₋₄alkyl,            C₁₋₄perhaloalkyl, and OC₁₋₄perhaloalkyl;    -   (b) phenyl substituted with two or three members each        independently selected from the group consisting of: Br, Cl, F,        C₁₋₄alkyl, C₁₋₄perhaloalkyl, and OC₁₋₄perhaloalkyl; and    -   (c) thienyl substituted with a member selected from the group        consisting of: Cl, CH₃, and CHF₂, CF₃.

-   47. The compound of embodiment 46, wherein R¹ is H, and R^(e) is H    or F.

-   48. A compound selected from the group consisting of:

-   1-(Pyrimidin-2-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   1-[(5-Bromo-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   5-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile;

-   1-[(2-Methylpyrimidin-5-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   1-(Pyrazin-2-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   1-(Pyrimidin-4-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   2-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-oxadiazole;

-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyloxazole;

-   2-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyloxazole;

-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;

-   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(1,1-Difluoroethyl)phenyl]-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-methyl-4H-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridine;

-   1-[(3-Methyl-1H-pyrazol-5-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   5-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-N-methyl-1,3,4-thiadiazol-2-amine;

-   5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazol-2-amine;

-   5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazol-2-ol;

-   5-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazol-2-amine;

-   N-(5-((6-(3-(Difluoromethoxy)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-1,3,4-thiadiazol-2-yl)acetamide;

-   3-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,2,4-oxadiazole;    1-Benzyl-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   1-[(3-Fluorophenyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;    3-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]benzonitrile;

-   1-[(4-Methoxyphenyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;    6-[3-(Trifluoromethyl)phenyl]-1-[[4-(trifluoromethyl)phenyl]methyl]pyrazolo[4,3-b]pyridine;

-   3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]benzonitrile;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(3,5-difluorophenyl)methyl]pyrazolo[4,3-b]pyridine;

-   3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-fluoro-benzonitrile;

-   3-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]benzonitrile;

-   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(3,5-difluorophenyl)methyl]pyrazolo[4,3-b]pyridine;

-   3-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-fluoro-benzonitrile;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-methyl-2-thienyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((5-fluorothiophen-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridine;

-   5-((6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)thiophene-2-carbonitrile;

-   6-[3-(1,1-Difluoroethyl)phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridine;

-   1-[(1-Methylimidazol-4-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   1-[(2,5-Dimethylpyrazol-3-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(1-methylpyrazol-3-yl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(1H-pyrazol-4-ylmethyl)pyrazolo[4,3-b]pyridine;

-   5-[[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-isoxazole;

-   3-[[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-isoxazole;

-   3-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]isoxazole;

-   3-[[6-[3-(1,1-Difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-isoxazole;

-   4-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]oxazole;

-   5-Methyl-3-[[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]isoxazole;

-   5-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-2-methyloxazole;

-   2-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyloxazole;

-   5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]isoxazole;

-   3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]isoxazole;

-   5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-isoxazole;

-   3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-isoxazole;

-   5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-2-methyloxazole;

-   4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-2-methyloxazole;

-   3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-4-methyl-isoxazole;

-   4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3,5-dimethyl-isoxazole;

-   3-[[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-isoxazole;

-   3-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-isoxazole;

-   5-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-2-methyloxazole;

-   2-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyloxazole;

-   3-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-isoxazole;

-   5-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-2-methyloxazole;

-   5-Methyl-3-[[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]isothiazole;

-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-thiazole;

-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-4-methyl-thiazole;

-   4-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-2-methyl-thiazole;

-   2-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-thiazole;

-   2-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-thiazole;

-   2-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-thiazole;

-   1-[(1-Methyl-1,2,4-triazol-3-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(1-methyltriazol-4-yl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(1-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(4-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(4,5-dimethyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-ethyl-4-methyl-1,2,4-triazol-3-yl)methyl]pyrazolo[4,3-b]pyridine;

-   2-[[6-(5-Chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;

-   2-Methyl-5-[[6-[5-(trifluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-oxadiazole;

-   2-[[6-[5-(Difluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;

-   5-[[6-(4-Fluorophenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole;

-   5-[[6-(3-Methoxyphenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole;

-   2-[[6-[3-(1,1-Difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;

-   2-[[6-[3-(1,1-Difluoroethyl)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;

-   3-Methyl-5-[[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,2,4-oxadiazole;

-   2-Methyl-5-[[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-oxadiazole;

-   5-Methyl-3-[[6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,2,4-oxadiazole;

-   5-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,2,4-oxadiazole;

-   2-Methyl-5-[[6-[2-(trifluoromethyl)-4-pyridyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-oxadiazole;

-   2-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;

-   2-[[3-Fluoro-6-(4-fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;

-   2-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-(trifluoromethyl)-1,3,4-oxadiazole;

-   2-[[6-(3-Chloro-4-fluoro-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;

-   2-[[6-(3-Chloro-4-fluoro-phenyl)-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;

-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-oxadiazole;

-   5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole;

-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;

-   3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,2,4-oxadiazole;

-   3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-4-methyl-1,2,5-oxadiazole;

-   2-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-oxadiazole;

-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-isopropyl-1,3,4-oxadiazole;

-   5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-N,N-dimethyl-1,3,4-oxadiazol-2-amine;

-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-(trifluoromethyl)-1,3,4-oxadiazole;

-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-phenyl-1,3,4-oxadiazole;

-   2-[[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;

-   2-[[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;

-   2-[[6-[4-Chloro-3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;

-   2-[[6-[4-Chloro-3-(difluoromethyl)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;

-   5-[[6-[3-Fluoro-5-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole;

-   5-[[6-[2-Fluoro-5-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole;

-   5-[[6-[4-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole;

-   5-[[6-[2-Fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole;

-   5-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-1,2,4-oxadiazole;

-   2-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;

-   3-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,2,4-oxadiazole;

-   2-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-(trifluoromethyl)-1,3,4-oxadiazole;

-   2-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;

-   2-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;

-   2-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;

-   2-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-(trifluoromethyl)-1,3,4-oxadiazole;

-   4-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]thiadiazole;

-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazole;

-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole;

-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole;

-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-methyl-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole;

-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-ethyl-1,3,4-thiadiazole;

-   5-((6-(3-(difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-N-methyl-1,3,4-thiadiazol-2-amine;

-   2-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methoxy-1,3,4-thiadiazole;

-   N-(5-((6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-1,3,4-thiadiazol-2-yl)acetamide;

-   2-(Difluoromethyl)-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazole;

-   2-Cyclopropyl-5-[[6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-1,3,4-thiadiazole;

-   2-[[6-[4-Chloro-3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole;

-   2-[[6-(4-Fluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole;

-   2-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole;

-   2-[[6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methoxy-1,3,4-thiadiazole;

-   2-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole;

-   2-[[6-(2,4-Difluoro-3-methyl-phenyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole;

-   6-(4-Methyl-2-thienyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   1-[(5-Methyl-3-pyridyl)methyl]-6-(4-methyl-2-thienyl)pyrazolo[4,3-b]pyridine;

-   6-(5-Methyl-2-thienyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   5-[[6-(5-Chloro-2-thienyl)pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile;

-   6-(3-Chloro-2-thienyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   5-[[6-[5-(Difluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile;

-   1-((6-Fluoropyridin-3-yl)methyl)-6-(5-(trifluoromethyl)thiophen-2-yl)-1H-pyrazolo[4,3-b]pyridine;

-   5-[[6-[5-(Trifluoromethyl)-2-thienyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile;

-   1-[(6-Fluoro-3-pyridyl)methyl]-6-(m-tolyl)pyrazolo[4,3-b]pyridine;

-   1-[(5-Fluoro-3-pyridyl)methyl]-6-(m-tolyl)pyrazolo[4,3-b]pyridine;

-   3-Fluoro-1-[(5-fluoro-3-pyridyl)methyl]-6-(m-tolyl)pyrazolo[4,3-b]pyridine;

-   6-(4-Chlorophenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(4-Fluorophenyl)-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   6-(4-Fluorophenyl)-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   1-[[5-(Difluoromethoxy)-3-pyridyl]methyl]-6-(4-fluorophenyl)pyrazolo[4,3-b]pyridine;

-   6-(3-Fluorophenyl)-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   6-(2-Fluorophenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(3-Methoxyphenyl)-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   1-[(6-Fluoro-3-pyridyl)methyl]-6-(3-methoxyphenyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)phenyl]-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   5-[[6-[3-(Difluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile;

-   1-[(5-Chloro-3-pyridyl)methyl]-6-[3-(difluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethoxy)phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(1,1-Difluoroethyl)phenyl]-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(1,1-Difluoroethyl)phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   1-(2-Pyridylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   1-(3-Pyridylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   1-(4-Pyridylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   1-[(6-Methyl-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   1-[(2-Methyl-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   1-[(5-Methyl-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   1-[(4-Methyl-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   1-[(6-Fluoro-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   1-[(2-Fluoro-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   1-[(5-Fluoro-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   1-[(2-Methoxy-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   1-[(5-Methoxy-3-pyridyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Trifluoromethyl)phenyl]-1-[[6-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Trifluoromethyl)phenyl]-1-[[5-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Trifluoromethyl)phenyl]-1-[[4-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridine;

-   6-(4-Fluoro-3-methyl-phenyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   3-Fluoro-6-(4-fluoro-3-methyl-phenyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   6-(4-Fluoro-3-methyl-phenyl)-1-[(2-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(4-Fluoro-3-methyl-phenyl)-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(4-Fluoro-3-methyl-phenyl)-1-[(4-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(4-Fluoro-3-methyl-phenyl)-1-[(6-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(4-Fluoro-3-methyl-phenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(3,5-Difluorophenyl)-1-[(4-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(3,5-Difluorophenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(3,4-Difluorophenyl)-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   6-(3,4-Difluorophenyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   6-(3,4-Difluorophenyl)-1-[(2-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(3,4-Difluorophenyl)-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(3,4-Difluorophenyl)-1-[(4-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(3,4-Difluorophenyl)-1-[(6-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(3,4-Difluorophenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(3,4-Difluorophenyl)-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   1-[[5-(Difluoromethoxy)-3-pyridyl]methyl]-6-(3,4-difluorophenyl)pyrazolo[4,3-b]pyridine;

-   6-(3-Chloro-4-fluoro-phenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(3-Chloro-4-fluoro-phenyl)-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-methyl-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(6-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(6-methoxy-2-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(2-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   1-[(5-Chloro-3-pyridyl)methyl]-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[[5-(difluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridine;

-   1-[[5-(Difluoromethoxy)-3-pyridyl]methyl]-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[[5-(trifluoromethyl)-3-pyridyl]methyl]pyrazolo[4,3-b]pyridine;

-   5-[[6-[3-(Difluoromethyl)-2-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile;

-   1-[(5-Chloro-3-pyridyl)methyl]-6-[3-(difluoromethyl)-2-fluoro-phenyl]pyrazolo[4,3-b]pyridine;

-   6-(3,4-Dichlorophenyl)-1-[(6-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(3,4-Dichlorophenyl)-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   5-[[6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile;

-   6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   1-[(5-Chloro-3-pyridyl)methyl]-6-[3-(1,1-difluoroethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   5-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile;

-   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(6-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(6-methoxy-2-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(2-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   1-[(5-Chloro-3-pyridyl)methyl]-6-[3-(difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridine;

-   6-[4-Chloro-3-(Difluoromethyl)phenyl]-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   1-[(5-Fluoro-3-pyridyl)methyl]-6-[4-fluoro-3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   6-[4-Fluoro-3-(trifluoromethyl)phenyl]-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(3-Bromo-4-fluorophenyl)-1-((6-fluoropyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine;

-   5-[[6-[4-Chloro-3-(1,1-difluoroethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile;

-   6-[4-Chloro-3-(1,1-difluoroethyl)phenyl]-1-[(5-chloro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   5-[[6-[4-Chloro-3-(difluoromethoxy)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]pyridine-3-carbonitrile;

-   6-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(5-methoxy-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[4-Chloro-3-(difluoromethoxy)phenyl]-1-[(5-chloro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(2,4-Difluoro-3-methyl-phenyl)-1-(2-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   6-(2,4-Difluoro-3-methyl-phenyl)-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   6-(2,4-Difluoro-3-methyl-phenyl)-1-[(5-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(2,4-Difluoro-3-methyl-phenyl)-1-[(4-methyl-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(2,4-Difluoro-3-methyl-phenyl)-1-[(6-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(2,4-Difluoro-3-methyl-phenyl)-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   1-(2-Pyridylmethyl)-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine;

-   1-[(5-Fluoro-3-pyridyl)methyl]-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine;

-   1-[(5-Methoxy-3-pyridyl)methyl]-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine;

-   1-[[5-(Difluoromethoxy)-3-pyridyl]methyl]-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine;

-   1-(Pyridazin-4-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   6-(m-Tolyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine;

-   6-(3-Fluorophenyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(1,1-Difluoroethyl)phenyl]-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine;

-   1-(Pyridazin-3-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   6-(4-Fluoro-3-methyl-phenyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(6-methylpyridazin-3-yl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(6-methylpyridazin-3-yl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine;

-   6-(3,4-Difluorophenyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine;

-   6-(4-Chloro-3-methyl-phenyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine;

-   1-(Pyridazin-3-ylmethyl)-6-(3,4,5-trifluorophenyl)pyrazolo[4,3-b]pyridine;

-   6-(2,4-Difluoro-3-methyl-phenyl)-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(pyrimidin-4-ylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(pyrimidin-4-ylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(pyrazin-2-ylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(pyrazin-2-ylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(1,1-Difluoroethyl)phenyl]-1-(pyrimidin-5-ylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(pyrimidin-5-ylmethyl)pyrazolo[4,3-b]pyridine;

-   1-(Pyrimidin-5-ylmethyl)-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(1,1-Difluoroethyl)-4-fluoro-phenyl]-1-(pyrimidin-5-ylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-(pyrimidin-5-ylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[4-Chloro-3-(difluoromethoxy)phenyl]-1-(pyrimidin-5-ylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(6-methylpyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(6-methylpyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(2-methylpyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine;

-   1-[(2-Methylpyrimidin-4-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(2-methylpyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(3,4-Difluorophenyl)-1-[(2-methylpyrimidin-5-yl)methyl]pyrazolo[4,3-b]pyridine;

-   6-(4-Chloro-3-methyl-phenyl)-1-[(2-methylpyrimidin-5-yl)methyl]pyrazolo[4,3-b]pyridine;

-   1-[(5-Methylpyrimidin-2-yl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(6-methoxypyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(6-methoxypyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(2-methoxypyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(2-methoxypyrimidin-4-yl)methyl]pyrazolo[4,3-b]pyridine;

-   (5-((6-(3-(Difluoromethyl)-4-fluorophenyl)-1H-pyrazolo[4,3-b]pyridin-1-yl)methyl)-1,3,4-oxadiazol-2-yl)methanol;

-   2-Fluoro-5-(1-((5-methyl-1,3,4-oxadiazol-2-yl)methyl)-1H-pyrazolo[4,3-b]pyridin-6-yl)benzoic    acid;

-   6-(3-(Difluoromethyl)-4-fluorophenyl)-1-((6-(fluoro-18F)pyridin-3-yl)methyl)-1H-pyrazolo[4,3-b]pyridine;

-   2-[[3-Bromo-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;

-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;    and

-   2-[[3-Deuterio-6-[3-(difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;    -   and pharmaceutically acceptable salts, N-oxides, or solvates        thereof.

-   49. A compound selected from the group consisting of:

-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyloxazole;

-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;

-   5-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-3-methyl-isoxazole;

-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]-3-fluoro-pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-oxadiazole;

-   3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,2,4-oxadiazole;

-   2-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-methyl-1,3,4-thiadiazole;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(3-pyridylmethyl)pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(5-fluoro-3-pyridyl)methyl]pyrazolo[4,3-b]pyridine;

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(pyridazin-3-ylmethyl)pyrazolo[4,3-b]pyridine;    and

-   6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-(pyrimidin-5-ylmethyl)pyrazolo[4,3-b]pyridine;    -   and pharmaceutically acceptable salts, N-oxides, or solvates        thereof.

-   50. A pharmaceutical composition comprising:    -   (A) an effective amount of at least one compound of Formula (I):

-   wherein-   R¹ is H, halo, or CH₃;-   Ar¹ is selected from the group consisting of:    -   (a) phenyl substituted with one member selected from the group        consisting of: halo, C₁₋₆alkyl, OC₁₋₆alkyl, C₁₋₆perhaloalkyl,        and OC₁₋₆perhaloalkyl;    -   (b) phenyl substituted with two or three members each        independently selected from the group consisting of: halo,        C₁₋₆alkyl, C₁₋₆perhaloalkyl, OC₁₋₆perhaloalkyl, and CO₂H; and    -   (c) thienyl substituted with a member selected from the group        consisting of: halo, C₁₋₆alkyl, and C₁₋₆perhaloalkyl; and        pyridine substituted with CF₃; and-   R² is selected from the group consisting of:    -   (d)

-   -   wherein        -   R^(a) is halo, C₁₋₆alkyl or CN;        -   R^(b) is H or C₁₋₂alkyl;        -   R^(c) is selected from the group consisting of: H,            C₁₋₆alkyl, C₁₋₆perhaloalkyl, CH₂OH, OC₁₋₆alkyl, OH, NH₂,            NH(CH₃), N(CH₃)₂, NH(C═O)CH₃, cyclopropyl, and phenyl;        -   X¹ is NCH₃, S or O;        -   X² is O, NH or NCH₃;        -   X³ is O or S;        -   X⁴ is NH or O;        -   X⁵ is NCH₃ or O;        -   X⁶ is NCH₃ or S;        -   and n is 2;    -   (e) phenyl; phenyl substituted with one or two members        independently selected from the group consisting of: halo,        OC₁₋₆alkyl, C₁₋₆perhaloalkyl, and CN; and    -   (f)

-   -   wherein        -   R^(d) is H or OC₁₋₆alkyl;        -   R^(e) is a member selected from the group consisting of: H,            halo, C₁₋₆alkyl, C₁₋₆perhaloalkyl, OC₁₋₆alkyl,            OC₁₋₆perhaloalkyl, and CN; and        -   R^(f) is H, C₁₋₆alkyl or OC₁₋₆alkyl;

-   and pharmaceutically acceptable salts, N-oxides or solvates of    compounds of Formula (I); (B) at least one pharmaceutically    acceptable excipient.

-   51. A pharmaceutical composition comprising an effective amount of    at least one compound of embodiment 50 and at least one    pharmaceutically acceptable excipient.

-   52. A method of treating a subject suffering from or diagnosed with    a disease, disorder, or medical condition mediated by GluN2B    receptor activity, comprising administering to a subject in need of    such treatment an effective amount of at least one compound selected    from compounds of Formula (I):

-   -   wherein    -   R¹ is H, halo, or CH₃;    -   Ar¹ is selected from the group consisting of:        -   (a) phenyl substituted with one member selected from the            group consisting of: halo, C₁₋₆alkyl, OC₁₋₆alkyl,            C₁₋₆perhaloalkyl, and OC₁₋₆perhaloalkyl;        -   (b) phenyl substituted with two or three members each            independently selected from the group consisting of: halo,            C₁₋₆alkyl, C₁₋₆perhaloalkyl, OC₁₋₆perhaloalkyl, and CO₂H;            and    -   (c) thienyl substituted with a member selected from the group        consisting of: halo, C₁₋₆alkyl, and C₁₋₆perhaloalkyl; and        pyridine substituted with CF₃; and    -   R² is selected from the group consisting of:    -   (d)

-   -   wherein        -   R^(a) is halo, C₁₋₆alkyl or CN;        -   R^(b) N is H or C₁₋₂alkyl;        -   R^(c) is selected from the group consisting of: H,            C₁₋₆alkyl, C₁₋₆perhaloalkyl, CH₂OH, OC₁₋₆alkyl, OH, NH₂,            NH(CH₃), N(CH₃)₂, NH(C═O)CH₃, cyclopropyl, and phenyl;        -   X¹ is NCH₃, S or C;        -   X² is O, NH or NCH₃;        -   X³ is O or S;        -   X⁴ is NH or;        -   X⁵ is NCH₃ or O;        -   X⁶ is NCH₃ or S;        -   and n is 2;    -   (e) phenyl; phenyl substituted with one or two members        independently selected from the group consisting of: halo,        OC₁₋₆alkyl, C₁₋₆perhaloalkyl, and CN; and    -   (f)

-   -   wherein        -   R^(d) is H or OC₁₋₆alkyl;    -   R^(e) is a member selected from the group consisting of: H,        halo, C₁₋₆alkyl, C₁₋₆perhaloalkyl, OC₁₋₆alkyl,        OC₁₋₆perhaloalkyl, and CN; and    -   R^(f) is H, C₁₋₆alkyl or OC₁₋₆alkyl;        and pharmaceutically acceptable salts, stereoisomers, isotopic        variants, N-oxides, or solvates of compounds of Formula (I).

-   53. The method of embodiment 52, wherein the disorder, disease or    condition mediated by the GluN2B receptor is selected from the group    consisting of: bipolar disorder, major depressive disorder,    treatment-resistant depression, post-partum depression, seasonal    affective disorder, Alzheimer's disease, Parkinson's disease,    Huntington's chorea, multiple sclerosis, cognitive impairment, head    injury, spinal cord injury, stroke, epilepsy, dyskinesias,    amyotrophic lateral sclerosis, neurodegeneration associated with    bacterial or chronic infections, pain, diabetic neuropathy,    migraine, cerebral ischemia, schizophrenia, encephalitis, autism and    autism spectrum disorders, memory and learning disorders, obsessive    compulsive disorder, attention deficit hyperactivity disorder (ADHD)    and addictive illnesses.

-   54. The method of embodiment 52 wherein the disorder, disease or    condition is selected from the group consisting of    treatment-resistant depression, major depressive disorder and    bipolar disorder.

The present disclosure is further exemplified by specific embodiments1-72 below.

-   1. A compound having the structure of Formula (I):

or a pharmaceutically acceptable salt, solvate, stereoisomer, isotopicvariant, or N-oxide thereof,whereinR¹ is H, halo, or CH₃;Ar¹ is selected from the group consisting of:

-   -   (a) phenyl substituted with one member selected from the group        consisting of: halo, C₁₋₆alkyl, OC₁₋₆alkyl, C₁₋₆perhaloalkyl,        and OC₁₋₆perhaloalkyl;    -   (b) phenyl substituted with two or three members each        independently selected from the group consisting of: halo,        C₁₋₆alkyl, C₁₋₆perhaloalkyl, OC₁₋₆perhaloalkyl, and CO₂H; and    -   (c) thienyl substituted with a member selected from the group        consisting of: halo, C₁₋₆alkyl, and C₁₋₆perhaloalkyl; and        pyridine substituted with CF₃; and        R² is selected from the group consisting of:    -   (d)

-   -   wherein        -   R^(a) is halo, C₁₋₆alkyl or CN;        -   R^(b) is H or C₁₋₂alkyl;        -   R^(c) is selected from the group consisting of: H,            C₁₋₆alkyl, C₁₋₆perhaloalkyl, CH₂OH, OC₁₋₆alkyl, OH, NH₂,            NH(CH₃), N(CH₃)₂, NH(C═O)CH₃, cyclopropyl, and phenyl;        -   X¹ is NCH₃, S or O;        -   X² is O, NH or NCH₃;        -   X³ is O or S;        -   X⁴ is NH or O;        -   X⁵ is NCH₃ or O;        -   X⁶ is NCH₃ or S;        -   and n is 2;    -   (e) phenyl; phenyl substituted with one or two members        independently selected from the group consisting of: halo,        OC₁₋₆alkyl, C₁₋₆perhaloalkyl, and CN; and    -   (f)

-   -   wherein        -   R^(d) is H or OC₁₋₆alkyl;        -   R^(e) is a member selected from the group consisting of H,            halo, C₁₋₆alkyl, C₁₋₆perhaloalkyl, OC₁₋₆alkyl,            OC₁₋₆perhaloalkyl, and CN; and        -   R^(f) is H, C₁₋₆alkyl or OC₁₋₆alkyl.

-   2. The compound of embodiment 1 or a pharmaceutically acceptable    salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof,    wherein R¹ is H.

-   3. The compound of embodiment 1 or a pharmaceutically acceptable    salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof,    wherein R¹ is F.

-   4. The compound of embodiment 1 or a pharmaceutically acceptable    salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof,    wherein R¹ is CH₃.

-   5. The compound of any one of embodiments 1 to 4, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein Ar¹ is

-   6. The compound of any one of embodiments 1 to 4, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein Ar¹ is phenyl substituted with    F, Cl, CH₃, OCH₃, CF₂H, CF₃, CF₂CH₃, or OCHF₂.-   7. The compound of any one of embodiments 1 to 4, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein Ar¹ is

-   8. The compound of any one of embodiments 1 to 4, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein Ar¹ is phenyl substituted with    two or three members independently selected from the group    consisting of: F, Cl, Br, CH₃, CF₂H, CF₃, CF₂CH₃, and OCHF₂.-   9. The compound of any one of embodiments 1 to 4, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein Ar¹ is

-   10. The compound of any one of embodiments 1 to 9, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R^(a) is F, CH₃ or CN.-   11. The compound of any one of embodiments 1 to 10, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R^(b) is H, CH₃ or CH₂CH₃.-   12. The compound of any one of embodiments 1 to 11, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R^(b) is H or CH₃.-   13. The compound of any one of embodiments 1 to 12, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R^(c) is H, CH₃, CH₂CH₃, CF₃,    OCH₃, OH, NH₂, NH(CH₃), N(CH₃)₂, NH(C═O)CH₃, cyclopropyl, or phenyl.-   14. The compound of any one of embodiments 1 to 13, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R^(d) is H. 15. The compound of    any one of embodiments 1 to 13, or a pharmaceutically acceptable    salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof,    wherein R^(d) is OCH₃.-   16. The compound of any one of embodiments 1 to 15, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R^(e) is H, Br, Cl, F, CH₃,    CF₂H, CF₃, OCH₃, OCF₂H, or CN.-   17. The compound of any one of embodiments 1 to 16, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R^(f) is H, CH₃, or OCH₃.-   18. The compound of any one of embodiments 1 to 18, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein X¹ is NCH₃.-   19. The compound of any one of embodiments 1 to 18, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein X¹ is O.-   20. The compound of any one of embodiments 1 to 18, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein X¹ is S.-   21. The compound of any one of embodiments 1 to 20, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein X² is O.-   22. The compound of any one of embodiments 1 to 20, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein X² is NH.-   23. The compound of any one of embodiments 1 to 20, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein X² is NCH₃.-   24. The compound of any one of embodiments 1 to 23, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein X³ is O.-   25. The compound of any one of embodiments 1 to 23, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein X³ is S.-   26. The compound of any one of embodiments 1 to 25, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein X⁴ is NH.-   27. The compound of any one of embodiments 1 to 25, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein X⁴ is O.-   28. The compound of any one of embodiments 1 to 27, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein X⁵ is NCH₃.-   29. The compound of any one of embodiments 1 to 27, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein X⁵ is O.-   30. The compound of any one of embodiments 1 to 29, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein X⁶ is NCH₃.-   31. The compound of any one of embodiments 1 to 29, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein X⁶ is S.-   32. The compound of any one of embodiments 1 to 31, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R² is

-   33. The compound of any one of embodiments 1 to 32, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R² is

-   34. The compound of any one of embodiments 1 to 32, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R² is

-   35. The compound of any one of embodiments 1 to 32, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R² is

-   36. The compound of any one of embodiments 1 to 32, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R² is

-   37. The compound of any one of embodiments 1 to 32, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R² is

-   38. The compound of any one of embodiments 1 to 32, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R² is

-   39. The compound of any one of embodiments 1 to 32, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R² is

-   40. The compound of any one of embodiments 1 to 32, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R² is

-   41. The compound of any one of embodiments 1 to 32, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R² is

-   42. The compound of any one of embodiments 1 to 32, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R² is

-   43. The compound of any one of embodiments 1 to 32, or a    pharmaceutically acceptable salt, solvate, stereoisomer, isotopic    variant, or N-oxide thereof, wherein R² is

-   44. The compound of embodiment 1 or a pharmaceutically acceptable    salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof,    having the structure of Formula (1A):

-   -   wherein    -   R¹ is H, F, or CH₃;    -   HAL is F or Cl;    -   R^(g) is selected from the group consisting of: H, Cl, CH₃,        CF₂H, CF₂CH₃, CF₃, and OCF₂H; and    -   Ring A is:        -   (a)

-   -   -    wherein R^(a) is F, CH₃ or CN;        -   (b)

-   -   -   (c)

-   -   -    or        -   (d)

-   -   -   X¹ is O, NCH₃ or S;        -   X³ is O or S;        -   X⁴ is NH or O;        -   X⁵ is NCH₃ or O;        -   R^(b) is H, CH₃, or CH₂CH₃;        -   R^(c) is selected from the group consisting of: H, CH₃,            CH₂CH₃, CH(CH₃)₂, CF₃, CHF₂, OCH₃, OH, NH₂, NH(CH₃),            N(CH₃)₂, NH(C═O)CH₃, cyclopropyl, and phenyl;        -   R^(d) is H or OCH₃; and        -   R^(f) is H, CH₃ or OCH₃.

-   45. The compound of embodiment 44 or a pharmaceutically acceptable    salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof,    wherein ring A is

-   46. The compound of embodiment 1 or a pharmaceutically acceptable    salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof,    having the structure of Formula (1B):

-   -   wherein    -   R¹ is H, F, or CH₃;    -   R^(e) is a member selected from the group consisting of: H, Br,        Cl, F, C₁₋₄alkyl, C₁₋₄perhaloalkyl, OC₁₋₄alkyl,        OC₁₋₄perhaloalkyl, and CN; and    -   Ar¹ is selected from the group consisting of:        -   (a) phenyl substituted with one member selected from the            group consisting of: Cl, F, C₁₋₄alkyl, OC₁₋₄alkyl,            C₁₋₄perhaloalkyl, and OC₁₋₄perhaloalkyl;        -   (b) phenyl substituted with two or three members each            independently selected from the group consisting of: Br, Cl,            F, C₁₋₄alkyl, C₁₋₄perhaloalkyl, and OC₁₋₄perhaloalkyl; and        -   (c) thienyl substituted with a member selected from the            group consisting of: Cl, CH₃, and CHF₂, CF₃.

-   47. The compound of embodiment 46 or a pharmaceutically acceptable    salt, solvate, stereoisomer, isotopic variant, or N-oxide thereof,    wherein R¹ is H, and R^(e) is H or F.

-   48. A compound selected from the compounds in Table 1 and    pharmaceutically acceptable salts, solvates, stereoisomers, isotopic    variants, and N-oxides thereof.

-   49. The compound of any one of embodiments 1 to 48, or a    pharmaceutically acceptable salt or solvate thereof.

-   50. The compound of any one of embodiments 1 to 48, or a    pharmaceutically acceptable salt or N-oxide thereof.

-   51. The compound of any one of embodiments 1 to 48, or a    pharmaceutically acceptable salt thereof.

-   52. The compound of any one of embodiments 1 to 48.

-   53. A pharmaceutically acceptable salt of the compound of any one of    embodiments 1 to 48.

-   54. A pharmaceutical composition comprising the compound of any one    of embodiments 1 to 48, or a pharmaceutically acceptable salt,    solvate, isotopic variant, or N-oxide thereof, and a    pharmaceutically acceptable excipient.

-   55. A pharmaceutical composition comprising the compound of any one    of embodiments 1 to 48, or a pharmaceutically acceptable salt or    solvate thereof, and a pharmaceutically acceptable excipient.

-   56. A pharmaceutical composition comprising the compound of any one    of embodiments 1 to 48, or a pharmaceutically acceptable salt or    N-oxide thereof, and a pharmaceutically acceptable excipient.

-   57. A pharmaceutical composition comprising the compound of any one    of embodiments 1 to 48, or a pharmaceutically acceptable salt    thereof, and a pharmaceutically acceptable excipient.

-   58. A pharmaceutical composition comprising the compound of any one    of embodiments 1 to 48 and a pharmaceutically acceptable excipient.

-   59. A pharmaceutical composition comprising a pharmaceutically    acceptable salt of the compound of any one of embodiments 1 to 48,    and a pharmaceutically acceptable excipient.

-   60. A unit dosage form comprising a therapeutically effective amount    of the pharmaceutical composition of any one of embodiments 54 to    59.

-   61. A method of treating a subject suffering from or diagnosed with    a disease, disorder, or medical condition mediated by GluN2B    receptor activity, comprising administering to the subject a    therapeutically effective amount of the compound of any one of    embodiments 1 to 48, or a pharmaceutically acceptable salt, solvate,    isotopic variant, or N-oxide thereof.

-   62. A method of treating a subject suffering from or diagnosed with    a disease, disorder, or medical condition mediated by GluN2B    receptor activity, comprising administering to the subject a    therapeutically effective amount of the compound of any one of    embodiments 1 to 48, or a pharmaceutically acceptable salt, or    solvate thereof.

-   63. A method of treating a subject suffering from or diagnosed with    a disease, disorder, or medical condition mediated by GluN2B    receptor activity, comprising administering to the subject a    therapeutically effective amount of the compound of any one of    embodiments 1 to 48, or a pharmaceutically acceptable salt or    N-oxide thereof.

-   64. A method of treating a subject suffering from or diagnosed with    a disease, disorder, or medical condition mediated by GluN2B    receptor activity, comprising administering to the subject a    therapeutically effective amount of the compound of any one of    embodiments 1 to 48, or a pharmaceutically acceptable salt thereof.

-   65. A method of treating a subject suffering from or diagnosed with    a disease, disorder, or medical condition mediated by GluN2B    receptor activity, comprising administering to the subject a    therapeutically effective amount of the pharmaceutical composition    of any one of embodiments 54 to 59 or the unit dosage form of    embodiment 60.

-   66. The method of any one of embodiments 61 to 65, wherein the    disease, disorder or medical condition mediated by GluN2B receptor    activity comprises bipolar disorder, major depressive disorder,    treatment-resistant depression, a mood disorder, post-partum    depression, seasonal affective disorder, Alzheimer's disease,    Parkinson's disease, Huntington's chorea, multiple sclerosis,    cognitive impairment, head injury, spinal cord injury, stroke,    epilepsy, dyskinesias, amyotrophic lateral sclerosis,    neurodegeneration associated with a bacterial or chronic infection,    pain, diabetic neuropathy, migraine, cerebral ischemia,    schizophrenia, encephalitis, autism or an autism spectrum disorder,    a memory disorder, a learning disorder, obsessive compulsive    disorder, attention deficit hyperactivity disorder (ADHD) or an    addictive illness.

-   67. The method of embodiment 66, wherein the disease, disorder or    medical condition mediated by GluN2B receptor activity comprises    bipolar disorder, a mood disorder, treatment resistant depression,    major depressive disorder, or epilepsy.

-   68. The method of embodiment 66, wherein the disease, disorder or    medical condition mediated by GluN2B receptor activity comprises    bipolar disorder.

-   69. The method of embodiment 66, wherein the disease, disorder or    medical condition mediated by GluN2B receptor activity comprises a    mood disorder.

-   70. The method of embodiment 66, wherein the disease, disorder or    medical condition mediated by GluN2B receptor activity comprises    treatment resistant depression.

-   71. The method of embodiment 66, wherein the disease, disorder or    medical condition mediated by GluN2B receptor activity comprises    major depressive disorder.

-   72. The method of embodiment 66, wherein the disease, disorder or    medical condition mediated by GluN2B receptor activity comprises    epilepsy.

1. A compound having the structure of Formula (I):

or a pharmaceutically acceptable salt or stereoisomer thereof, wherein:R¹ is H, halo, or CH₃; Ar¹ is selected from the group consisting of: (a)phenyl substituted with one member selected from the group consistingof: halo, C₁₋₆alkyl, OC₁₋₆alkyl, C₁₋₆perhaloalkyl, andOC₁₋₆perhaloalkyl; (b) phenyl substituted with two or three members eachindependently selected from the group consisting of: halo, C₁₋₆alkyl,C₁₋₆perhaloalkyl, OC₁₋₆perhaloalkyl, and CO₂H; and (c) thienylsubstituted with a member selected from the group consisting of: halo,C₁₋₆alkyl, and C₁₋₆perhaloalkyl; and pyridine substituted with CF₃; andR² is:


2. The compound of claim 1 or a pharmaceutically acceptable salt orstereoisomer thereof, wherein R¹ is H.
 3. The compound of claim 1 or apharmaceutically acceptable salt or stereoisomer thereof, wherein R¹ isF.
 4. The compound of claim 1 or a pharmaceutically acceptable salt orstereoisomer thereof, wherein R¹ is CH₃.
 5. The compound of claim 1 or apharmaceutically acceptable salt or stereoisomer thereof, wherein Ar¹ is


6. The compound of claim 1 or a pharmaceutically acceptable salt orstereoisomer thereof, wherein Ar¹ is phenyl substituted with F, Cl, CH₃,OCH₃, CF₂H, CF₃, CF₂CH₃, or OCHF₂.
 7. The compound of claim 1 or apharmaceutically acceptable salt or stereoisomer thereof, wherein Ar¹ is


8. The compound of claim 1 or a pharmaceutically acceptable salt orstereoisomer thereof, wherein Ar¹ is phenyl substituted with two orthree members independently selected from the group consisting of: F,Cl, Br, CH₃, CF₂H, CF₃, CF₂CH₃, and OCHF₂.
 9. The compound of claim 1 ora pharmaceutically acceptable salt or stereoisomer thereof, wherein Ar¹is

10-25. (canceled)
 26. A compound selected from the group consisting of:1-Benzyl-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;1-[(3-Fluorophenyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;3-[[6-[3-(Trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]benzonitrile;1-[(4-Methoxyphenyl)methyl]-6-[3-(trifluoromethyl)phenyl]pyrazolo[4,3-b]pyridine;6-[3-(Trifluoromethyl)phenyl]-1-[[4-(trifluoromethyl)phenyl]methyl]pyrazolo[4,3-b]pyridine;3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]benzonitrile;6-[3-(Difluoromethyl)-4-fluoro-phenyl]-1-[(3,5-difluorophenyl)methyl]pyrazolo[4,3-b]pyridine;3-[[6-[3-(Difluoromethyl)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-fluoro-benzonitrile;3-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]benzonitrile;6-[3-(Difluoromethoxy)-4-fluoro-phenyl]-1-[(3,5-difluorophenyl)methyl]pyrazolo[4,3-b]pyridine;3-[[6-[3-(Difluoromethoxy)-4-fluoro-phenyl]pyrazolo[4,3-b]pyridin-1-yl]methyl]-5-fluoro-benzonitrile;and pharmaceutically acceptable salts and stereoisomers thereof. 27.(canceled)
 28. A pharmaceutical composition comprising: (A) at least onecompound selected from compounds of Formula (I):

and pharmaceutically acceptable salts and stereoisomers of compounds ofFormula (I), wherein: R¹ is H, halo, or CH₃; Ar¹ is selected from thegroup consisting of: (a) phenyl substituted with one member selectedfrom the group consisting of: halo, C₁₋₆alkyl, OC₁₋₆alkyl,C₁₋₆perhaloalkyl, and OC₁₋₆perhaloalkyl; (b) phenyl substituted with twoor three members each independently selected from the group consistingof: halo, C₁₋₆alkyl, C₁₋₆perhaloalkyl, OC₁₋₆perhaloalkyl, and CO₂H; and(c) thienyl substituted with a member selected from the group consistingof: halo, C₁₋₆alkyl, and C₁₋₆perhaloalkyl; and pyridine substituted withCF₃; and R² is:

 and (B) at least one pharmaceutically acceptable excipient. 29-31.(canceled)
 32. A pharmaceutical composition comprising the compound ofclaim 26 or a pharmaceutically acceptable salt thereof or stereoisomerthereof and at least one pharmaceutically acceptable excipient.
 33. Amethod of treating a subject suffering from or diagnosed withtreatment-resistant depression, comprising administering to the subjectan effective amount of the compound of claim 1 or a pharmaceuticallyacceptable salt or stereoisomer thereof.
 34. A method of treating asubject suffering from or diagnosed with major depressive disorder,comprising administering to the subject an effective amount of thecompound of claim 1 or a pharmaceutically acceptable salt orstereoisomer thereof.
 35. A method of treating a subject suffering fromor diagnosed with treatment-resistant depression, comprisingadministering to the subject an effective amount of the compound ofclaim 26 or a pharmaceutically acceptable salt or stereoisomer thereof.36. A method of treating a subject suffering from or diagnosed withmajor depressive disorder, comprising administering to the subject aneffective amount of the compound of claim 26 or a pharmaceuticallyacceptable salt or stereoisomer thereof.
 37. A method of treating asubject suffering from or diagnosed with treatment-resistant depression,comprising administering to the subject an effective amount of thepharmaceutical composition of claim
 28. 38. A method of treating asubject suffering from or diagnosed with major depressive disorder,comprising administering to the subject an effective amount of thepharmaceutical composition of claim
 28. 39. A method of treating asubject suffering from or diagnosed with treatment-resistant depression,comprising administering to the subject an effective amount of thepharmaceutical composition of claim
 32. 40. A method of treating asubject suffering from or diagnosed with major depressive disorder,comprising administering to the subject an effective amount of thepharmaceutical composition of claim 32.